Inhibitors of bruton&#39;s tyrosine kinase

ABSTRACT

Disclosed herein are reversible and irreversible inhibitors of Bruton&#39;s tyrosine kinase (Btk). Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are described, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

CROSS-REFERENCE

This application is a continuation of U.S. U.S. application Ser. No.15/485,654, filed Apr. 12, 2017, which is a continuation of U.S.application Ser. No. 15/173,182, filed Jun. 3, 2016, which is acontinuation of U.S. application Ser. No. 14/559,889, filed Dec. 3,2014, which claims the benefit of U.S. Provisional Application No.61/912,483, filed Dec. 5, 2013. Each of these applications isincorporated herein by reference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Oct. 6, 2017, isnamed PIR-88004_SL.txt and is 1,076 bytes in size.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments containing such compounds,and methods of using such compounds and compositions to inhibit theactivity of tyrosine kinases.

BACKGROUND OF THE INVENTION

Bruton's tyrosine kinase (Btk), a member of the Tec family ofnon-receptor tyrosine kinases, is a key signaling enzyme expressed inall hematopoietic cells types except T lymphocytes and natural killercells. Btk plays an essential role in the B-cell signaling pathwaylinking cell surface B-cell receptor (BCR) stimulation to downstreamintracellular responses.

Btk is a key regulator of B-cell development, activation, signaling, andsurvival (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer andSchwartzberg, Curr Op Imm 2000, 282-288). In addition, Btk plays a rolein a number of other hematopoetic cell signaling pathways, e.g., Tolllike receptor (TLR) and cytokine receptor-mediated TNF-α production inmacrophages, IgE receptor (FcepsilonRI) signaling in Mast cells,inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells,and collagen-stimulated platelet aggregation. See, e.g., C. A. Jeffries,et al., (2003), Journal of Biological Chemistry 278:26258-26264; N. J.Horwood, et al., (2003), The Journal of Experimental Medicine197:1603-1611; Iwaki et al. (2005), Journal of Biological Chemistry280(48):40261-40270; Vassilev et al. (1999), Journal of BiologicalChemistry 274(3): 1646-1656, and Quek et al. (1998), Current Biology8(20): 1137-1140.

SUMMARY OF THE INVENTION

Described herein are inhibitors of Bruton's tyrosine kinase (Btk). Alsodescribed herein are irreversible inhibitors of Btk. Also describedherein are reversible inhibitors of Btk. Further described areirreversible inhibitors of Btk that form a covalent bond with a cysteineresidue on Btk. Further described herein are irreversible inhibitors ofother tyrosine kinases, wherein the other tyrosine kinases sharehomology with Btk by having a cysteine residue (including a Cys 481residue) that can form a covalent bond with the irreversible inhibitor(such tyrosine kinases, are referred herein as “Btk tyrosine kinasecysteine homologs”).

Also described herein are methods for synthesizing such reversible orirreversible inhibitors, methods for using such reversible orirreversible inhibitors in the treatment of diseases (including diseaseswherein irreversible inhibition of Btk provides therapeutic benefit to apatient having the disease). Further described are pharmaceuticalformulations that include a reversible or irreversible inhibitor of Btk.

In one aspect, provided herein is a compound of Formula (IA) having thestructure:

wherein:

ring A is substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;

W is —C(R₂)— or —N—; X is —C(R₂)— or —N—;

Y is optionally present and when present is —CH₂O—, —OCH₂—, —OCH₂CH₂O—,—O—, —N(R₃)—, —C(O)—, —N(R₃)C(O)—, —C(O)N(R₃)—, —N(R₃)C(O)N(R₃)—,—S(O)—, —S(O)₂—, —N(R₃)S(O)₂—, —S(O)₂N(R₃)—, —C(═NH)—, —C(═NH)N(R₃)—,—C(═NH)N(R₃)—, or substituted or unsubstituted C₁-C₄alkylene; Z isoptionally present and when present is substituted or unsubstitutedC₁-C₃alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;

G is

R₁ is —R₄, —CH₂R₄, —C(O)R₉, —C(O)C(O)R₉, —C(O)OR₄, —C(O)N(R₃)(R₄), or—S(O)₂R₉;R_(1′) is —C(O)R_(9′), —C(O)C(O)R₉, —C(O)OR₄, —C(O)N(R₃)(R₄), or—S(O)₂R₉;each R₂ is independently H, substituted or unsubstituted C₁-C₄alkyl,—CN, or halogen;each R₃ is independently is H, or substituted or unsubstitutedC₁-C₄alkyl;each R₄ is independently H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;R₅ is H, substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl; or R₁ and R₅ togetherwith the nitrogen atom to which they are attached are combined to form asubstituted or unsubstituted C₂-C₉heterocycloalkyl ring;each R₆ is independently halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂; or R₁ and R₆ arecombined to form a substituted or unsubstituted C₂-C₉heterocycloalkylring;each R₇ is independently halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂;R₉ is —R₄, or

R₁₀ is H, halogen, —CN, or -L₁-L₂;R₁₁ and R₁₂ are independently H, halogen, —CN, or -L₁-L₂; or R₁₁ and R₁₂taken together form a bond;each L₁ is optionally present and when present each L₁ is independentlysubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂aryl, substituted or unsubstituted C₁-C₁₂heteroaryl,—C(═O)—, —O—, or —S—; each L₂ is independently H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, substituted or unsubstituted C₁-C₁₂heteroaryl or —N(R₁₃)₂;each R₁₃ is independently H, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₂-C₇ heterocycloalkyl, C₆-C₁₂aryl, orC₁-C₁₂heteroaryl;n is 0-3;p is 0-3; andq is 0-3;or a pharmaceutically acceptable solvate, pharmaceutically acceptablesalt, or pharmaceutically acceptable prodrug thereof;provided thati) when W is N, and R₁ is H, t-Boc, or —C(O)—CH═CH₂; then X is otherthan C-Et or N; andii) when W is N, G is

then X is CH or N;iii) when W is N, and X is CH; then R_(1′) is other than —C(O)Me, ort-Boc; andiv) when n is 0; then each of p and q is independently 0, 1, or 2.

In another aspect, provided herein is a compound of Formula (I) havingthe structure:

wherein:

ring A is substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;

W is —C(R₂)— or —N—; X is —C(R₂)— or —N—;

Y is optionally present and when present is —CH₂O—, —OCH₂—, —OCH₂CH₂O—,—O—, —N(R₃)—, —C(O)—, —N(R₃)C(O)—, —C(O)N(R₃)—, —N(R₃)C(O)N(R₃)—,—S(O)—, —S(O)₂—, —N(R₃)S(O)₂—, —S(O)₂N(R₃)—, —C(═NH)—, —C(═NH)N(R₃)—, orsubstituted or unsubstituted C₁-C₄alkylene;Z is optionally present and when present is substituted or unsubstitutedC₁-C₃alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;

G is

R₁ is —R₄, —CH₂R₄, —C(O)R₉, —C(O)C(O)R₉, —C(O)OR₄, —C(O)N(R₃)(R₄), or—S(O)₂R₉; each R₂ is independently H, —CN, or halogen;each R₃ is independently is H, or substituted or unsubstitutedC₁-C₄alkyl;each R₄ is independently H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;R₅ is H, substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl; or R₁ and R₅ togetherwith the nitrogen atom to which they are attached are combined to form asubstituted or unsubstituted C₂-C₉heterocycloalkyl ring; each R₆ isindependently halogen, —CN, —OH, —NH₂, substituted or unsubstitutedC₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₆heterocycloalkyl, or —N(R₃)₂; or R₁ and R₆ are combined to form asubstituted or unsubstituted C₂-C₉heterocycloalkyl ring;each R₇ is independently halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂;R₉ is —R₄, or

R₁₀ is H, halogen, —CN, or -L₁-L₂;R₁₁ and R₁₂ are independently H, halogen, —CN, or -L₁-L₂; or R₁₁ and R₁₂taken together form a bond;each L₁ is optionally present and when present each L₁ is independentlysubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂aryl, substituted or unsubstituted C₁-C₁₂heteroaryl,—C(═O)—, —O—, or —S—; each L₂ is independently H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, substituted or unsubstituted C₁-C₁₂heteroaryl or —N(R₁₃)₂;each R₁₃ is independently H, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₂-C₇ heterocycloalkyl, C₆-C₁₂aryl, orC₁-C₁₂heteroaryl;p is 0-3; andq is 0-3;or a pharmaceutically acceptable solvate, pharmaceutically acceptablesalt, or pharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (IA) or (I) wherein ring A issubstituted or unsubstituted C₆-C₁₂aryl. In another embodiment is acompound of Formula (IA) or (I) wherein ring A is phenyl. In anotherembodiment is a compound of Formula (IA) or (I) wherein Y is absent,—CH₂O—, —OCH₂—, —O—, —N(R₃)—, —C(O)—, —N(R₃)C(O)—, —C(O)N(R₃)—, orsubstituted or unsubstituted C₁-C₄alkylene. In another embodiment is acompound of Formula (IA) or (I) wherein Y is absent, —C(O)—, or—C(O)N(R₃)—. In another embodiment is a compound of Formula (IA) or (I)wherein Z is substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₆-C₁₂aryl, or substituted or unsubstitutedC₁-C₁₂heteroaryl. In another embodiment is a compound of Formula (IA) or(I) wherein R₁ is —C(O)R₉. In another embodiment is a compound ofFormula (IA) or (I) wherein R₉ is —R₄, and R₄ is substituted orunsubstituted C₆-C₁₂aryl, or substituted or unsubstitutedC₁-C₁₂heteroaryl.

In another embodiment is a compound of Formula (IA) or (I) wherein ringA is substituted or unsubstituted C₁-C₁₂heteroaryl. In anotherembodiment is a compound of Formula (IA) or (I) wherein ring A ispyridyl. In another embodiment is a compound of Formula (IA) or (I)wherein Y is absent, —CH₂O—, —OCH₂—, —O—, —N(R₃)—, —C(O)—, —N(R₃)C(O)—,—C(O)N(R₃)—, or substituted or unsubstituted C₁-C₄alkylene. In anotherembodiment is a compound of Formula (IA) or (I) wherein Y is absent,—C(O)—, or —C(O)N(R₃)—. In another embodiment is a compound of Formula(IA) or (I) wherein Z is substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl. In another embodiment isa compound of Formula (IA) or (I) wherein R₁ is —C(O)R₉. In anotherembodiment is a compound of Formula (IA) or (I) wherein R₉ is —R₄, andR₄ is substituted or unsubstituted C₆-C₁₂aryl, or substituted orunsubstituted C₁-C₁₂heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IA) or (I) wherein X is —C(H)—. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IA) or (I)wherein X is —N—. In a further embodiment of the aforementionedembodiments is a compound of Formula (IA) or (I) wherein W is —C(H)—. Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IA) or (I) wherein W is —N—.

In another aspect is a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (IA) or (I) ora pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof, and a pharmaceuticallyacceptable excipient. In one embodiment, the pharmaceutical compositioncomprising the compound of Formula (IA) or (I) or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof, is formulated for a routeof administration selected from oral administration, parenteraladministration, buccal administration, nasal administration, topicaladministration, or rectal administration.

In another aspect is a method for treating an autoimmune disease orcondition comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (IA) or (I) ora pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof. In one embodiment theautoimmune disease is selected from rheumatoid arthritis or lupus. In afurther aspect is a method for treating a heteroimmune disease orcondition comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (IA) or (I) ora pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof. In yet anotherembodiment is a method for treating a cancer comprising administering toa patient in need a therapeutically effective amount of a compound ofFormula (IA) or (I) or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or pharmaceutically acceptableprodrug thereof. In one embodiment the cancer is a B-cell proliferativedisorder. In another embodiment the B-cell proliferative disorder isdiffuse large B cell lymphoma, follicular lymphoma, mantel celllymphoma, or chronic lymphocytic leukemia.

In yet a further aspect is a method for treating mastocytosis comprisingadministering to a patient in need a therapeutically effective amount ofa compound of Formula (I) or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or pharmaceutically acceptableprodrug thereof.

In another aspect is a method for treating osteoporosis or boneresorption disorders comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (I) or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof.

In a further aspect is a method for treating an inflammatory disease orcondition comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (I) or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof.

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

In a further aspect are provided pharmaceutical compositions, whichinclude a therapeutically effective amount of at least one of any of thecompounds herein, or a pharmaceutically acceptable salt,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate. In certain embodiments, compositions provided herein furtherinclude a pharmaceutically acceptable diluent, excipient and/or binder.

Pharmaceutical compositions formulated for administration by anappropriate route and means containing effective concentrations of oneor more of the compounds provided herein, or pharmaceutically effectivederivatives thereof, that deliver amounts effective for the treatment,prevention, or amelioration of one or more symptoms of diseases,disorders or conditions that are modulated or otherwise affected bytyrosine kinase activity, or in which tyrosine kinase activity isimplicated, are provided. The effective amounts and concentrations areeffective for ameliorating any of the symptoms of any of the diseases,disorders or conditions disclosed herein.

In certain embodiments, provided herein is a pharmaceutical compositioncontaining: i) a physiologically acceptable carrier, diluent, and/orexcipient; and ii) one or more compounds provided herein.

In one aspect, provided herein are methods for treating a patient byadministering a compound provided herein. In some embodiments, providedherein is a method of inhibiting the activity of tyrsoine kinase(s),such as Btk, or of treating a disease, disorder, or condition, whichwould benefit from inhibition of tyrosine kinase(s), such as Btk, in apatient, which includes administering to the patient a therapeuticallyeffective amount of at least one of any of the compounds herein, orpharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate.

In another aspect, provided herein is the use of a compound disclosedherein for inhibiting Bruton's tyrosine kinase (Btk) activity or for thetreatment of a disease, disorder, or condition, which would benefit frominhibition of Bruton's tyrosine kinase (Btk) activity.

In some embodiments, compounds provided herein are administered to ahuman.

In some embodiments, compounds provided herein are orally administered.

In other embodiments, compounds provided herein are used for theformulation of a medicament for the inhibition of tyrosine kinaseactivity. In some other embodiments, compounds provided herein are usedfor the formulation of a medicament for the inhibition of Bruton'styrosine kinase (Btk) activity.

Articles of manufacture including packaging material, a compound orcomposition or pharmaceutically acceptable derivative thereof providedherein, which is effective for inhibiting the activity of tyrosinekinase(s), such as Btk, within the packaging material, and a label thatindicates that the compound or composition, or pharmaceuticallyacceptable salt, pharmaceutically acceptable prodrug, orpharmaceutically acceptable solvate thereof, is used for inhibiting theactivity of tyrosine kinase(s), such as Btk, are provided.

In a further aspect, provided herein is a method for inhibiting Bruton'styrosine kinase in a subject in need thereof by administering to thesubject thereof a composition containing a therapeutically effectiveamount of at least one compound having the structure of Formula (IA),(I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb). In someembodiments, the subject in need is suffering from an autoimmunedisease, e.g., inflammatory bowel disease, arthritis, lupus, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barre syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behçet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, or vulvodynia.

In other embodiments, the subject in need is suffering from aheteroimmune condition or disease, e.g., graft versus host disease,transplantation, transfusion, anaphylaxis, allergy, type Ihypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopicdermatitis.

In certain embodiments, the subject in need is suffering from aninflammatory disease, e.g., asthma, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In further embodiments, the subject in need is suffering from a cancer.In one embodiment, the cancer is a B-cell proliferative disorder, e.g.,diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocyticlymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenicmarginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodalmarginal zone B cell lymphoma, nodal marginal zone B cell lymphoma,mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma,intravascular large B cell lymphoma, primary effusion lymphoma, burkittlymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments,where the subject is suffering from a cancer, an anti-cancer agent isadministered to the subject in addition to one of the above-mentionedcompounds. In one embodiment, the anti-cancer agent is an inhibitor ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002.

In further embodiments, the subject in need is suffering from athromboembolic disorder, e.g., myocardial infarct, angina pectoris,reocclusion after angioplasty, restenosis after angioplasty, reocclusionafter aortocoronary bypass, restenosis after aortocoronary bypass,stroke, transitory ischemia, a peripheral arterial occlusive disorder,pulmonary embolism, or deep venous thrombosis.

In a further aspect, provided herein is a method for treating anautoimmune disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (IA), Formula (I), Formula(Ia), Formula (II), Formula (III), Formula (IV), Formula (Va)-(Vh), orFormula (VIa)-(VIb). In one embodiment, the autoimmune disease isarthritis. In another embodiment, the autoimmune disease is lupus. Insome embodiments, the autoimmune disease is inflammatory bowel disease(including Crohn's disease and ulcerative colitis), rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barre syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis. Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behçet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, or vulvodynia.

In a further aspect, provided herein is a method for treating aheteroimmune condition or disease by administering to a subject in needthereof a composition containing a therapeutically effective amount ofat least one compound having the structure of Formula (IA), Formula (I),Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb). In some embodiments, the heteroimmunecondition or disease is graft versus host disease, transplantation,transfusion, anaphylaxis, allergy, type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, or atopic dermatitis.

In a further aspect, provided herein is a method for treating aninflammatory disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (IA), Formula (I), Formula(Ia), Formula (II), Formula (III), Formula (IV), Formula (Va)-(Vh), orFormula (VIa)-(VIb). In some embodiments, the inflammatory disease isasthma, inflammatory bowel disease (including Crohn's disease andulcerative colitis), appendicitis, blepharitis, bronchiolitis,bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis,conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,mastitis, meningitis, myelitis myocarditis, myositis, nephritis,oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis,tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In yet another aspect, provided herein is a method for treating a cancerby administering to a subject in need thereof a composition containing atherapeutically effective amount of at least one compound having thestructure of Formula (IA), Formula (I), Formula (Ia), Formula (II),Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb).In one embodiment, the cancer is a B-cell proliferative disorder, e.g.,diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocyticlymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenicmarginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodalmarginal zone B cell lymphoma, nodal marginal zone B cell lymphoma,mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma,intravascular large B cell lymphoma, primary effusion lymphoma, burkittlymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments,where the subject is suffering from a cancer, an anti-cancer agent isadministered to the subject in addition to one of the above-mentionedcompounds. In one embodiment, the anti-cancer agent is an inhibitor ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002.

In another aspect, provided herein is a method for treating athromboembolic disorder by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (IA), Formula (I), Formula(Ia), Formula (II), Formula (III), Formula (IV), Formula (Va)-(Vh), orFormula (VIa)-(VIb). In some embodiments, the thromboembolic disorder ismyocardial infarct, angina pectoris, reocclusion after angioplasty,restenosis after angioplasty, reocclusion after aortocoronary bypass,restenosis after aortocoronary bypass, stroke, transitory ischemia, aperipheral arterial occlusive disorder, pulmonary embolism, or deepvenous thrombosis.

In a further aspect, provided herein is a method for treating anautoimmune disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of a compoundthat forms a covalent bond with Bruton's tyrosine kinase. In oneembodiment, the compound forms a covalent bond with the activated formof Bruton's tyrosine kinase. In further or alternative embodiments, thecompound irreversibly inhibits the Bruton's tyrosine kinase to which itis covalently bound. In a further or alternative embodiment, thecompound forms a covalent bond with a cysteine residue on Bruton'styrosine kinase.

In a further aspect, provided herein is a method for treating aheteroimmune condition or disease by administering to a subject in needthereof a composition containing a therapeutically effective amount of acompound that forms a covalent bond with Bruton's tyrosine kinase. Inone embodiment, the compound forms a covalent bond with the activatedform of Bruton's tyrosine kinase. In further or alternative embodiments,the compound irreversibly inhibits the Bruton's tyrosine kinase to whichit is covalently bound. In a further or alternative embodiment, thecompound forms a covalent bond with a cysteine residue on Bruton'styrosine kinase.

In a further aspect, provided herein is a method for treating aninflammatory disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of a compoundthat forms a covalent bond with Bruton's tyrosine kinase. In oneembodiment, the compound forms a covalent bond with the activated formof Bruton's tyrosine kinase. In further or alternative embodiments, thecompound irreversibly inhibits the Bruton's tyrosine kinase to which itis covalently bound. In a further or alternative embodiment, thecompound forms a covalent bond with a cysteine residue on Bruton'styrosine kinase. In yet another aspect, provided herein is a method fortreating a cancer by administering to a subject in need thereof acomposition containing a therapeutically effective amount of a compoundthat forms a covalent bond with Bruton's tyrosine kinase. In oneembodiment, the compound forms a covalent bond with the activated formof Bruton's tyrosine kinase. In further or alternative embodiments, thecompound irreversibly inhibits the Bruton's tyrosine kinase to which itis covalently bound. In a further or alternative embodiment, thecompound forms a covalent bond with a cysteine residue on Bruton'styrosine kinase.

In another aspect, provided herein is a method for treating athromboembolic disorder by administering to a subject in need thereof acomposition containing a therapeutically effective amount of a compoundthat forms a covalent bond with Bruton's tyrosine kinase. In oneembodiment, the compound forms a covalent bond with the activated formof Bruton's tyrosine kinase. In further or alternative embodiments, thecompound irreversibly inhibits the Bruton's tyrosine kinase to which itis covalently bound. In a further or alternative embodiment, thecompound forms a covalent bond with a cysteine residue on Bruton'styrosine kinase.

In another aspect are methods for modulating, including irreversiblyinhibiting the activity of Btk or other tyrosine kinases, wherein theother tyrosine kinases share homology with Btk by having a cysteineresidue (including a Cys 481 residue) that can form a covalent bond withat least one irreversible inhibitor described herein, in a mammalcomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (IA), Formula(I), Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb). In another aspect are methods formodulating, including including reversibly or irreversibly inhibiting,the activity of Btk in a mammal comprising administering to the mammalat least once an effective amount of at least one compound having thestructure of Formula (IA), Formula (I), Formula (Ia), Formula (II),Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb).In another aspect are methods for treating Btk-dependent or Btk mediatedconditions or diseases, comprising administering to the mammal at leastonce an effective amount of at least one compound having the structureof Formula (IA), Formula (I), Formula (Ia), Formula (II), Formula (III),Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb).

In another aspect are methods for treating inflammation comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (IA), Formula (I),Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb).

A further aspect are methods for the treatment of cancer comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (IA), Formula (I),Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb). The type of cancer may include, butis not limited to, pancreatic cancer and other solid or hematologicaltumors.

In another aspect are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (IA), Formula(I), Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb). In a further embodiment of thisaspect, the respiratory disease is asthma. In a further embodiment ofthis aspect, the respiratory disease includes, but is not limited to,adult respiratory distress syndrome and allergic (extrinsic) asthma,non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma,clinical asthma, nocturnal asthma, allergen-induced asthma,aspirin-sensitive asthma, exercise-induced asthma, isocapnichyperventilation, child-onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, and seasonalasthma.

In another aspect are methods for preventing rheumatoid arthritis andosteoarthritis comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (IA), Formula (I), Formula (Ia), Formula (II), Formula (III),Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb).

In another aspect are methods for treating inflammatory responses of theskin comprising administering to the mammal at least once an effectiveamount of at least one compound having the structure of Formula (IA),Formula (I), Formula (Ia), Formula (II), Formula (III), Formula (IV),Formula (Va)-(Vh), or Formula (VIa)-(VIb). Such inflammatory responsesof the skin include, by way of example, dermatitis, contact dermatitis,eczema, urticaria, rosacea, and scarring. In another aspect are methodsfor reducing psoriatic lesions in the skin, joints, or other tissues ororgans, comprising administering to the mammal an effective amount of afirst compound having the structure of Formula (IA), Formula (I),Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb).

In another aspect is the use of a compound of Formula (IA), Formula (I),Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb), in the manufacture of a medicamentfor treating an inflammatory disease or condition in an animal in whichthe activity of Btk or other tyrosine kinases, wherein the othertyrosine kinases share homology with Btk by having a cysteine residue(including a Cys 481 residue) that can form a covalent bond with atleast one irreversible inhibitor described herein, contributes to thepathology and/or symptoms of the disease or condition. In one embodimentof this aspect, the tyrosine kinase protein is Btk. In another orfurther embodiment of this aspect, the inflammatory disease orconditions are respiratory, cardiovascular, or proliferative diseases.

In any of the aforementioned aspects are further embodiments in whichadministration is enteral, parenteral, or both, and wherein (a) theeffective amount of the compound is systemically administered to themammal; (b) the effective amount of the compound is administered orallyto the mammal; (c) the effective amount of the compound is intravenouslyadministered to the mammal; (d) the effective amount of the compoundadministered by inhalation; (e) the effective amount of the compound isadministered by nasal administration; or (f) the effective amount of thecompound is administered by injection to the mammal; (g) the effectiveamount of the compound is administered topically (dermal) to the mammal;(h) the effective amount of the compound is administered by ophthalmicadministration; or (i) the effective amount of the compound isadministered rectally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredto the mammal once; (ii) the compound is administered to the mammalmultiple times over the span of one day; (iii) the compound isadministered to the mammal continually; or (iv) the compound isadministered to the mammal continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredin a single dose; (ii) the time between multiple administrations isevery 6 hours; (iii) the compound is administered to the mammal every 8hours. In further or alternative embodiments, the method comprises adrug holiday, wherein the administration of the compound is temporarilysuspended or the dose of the compound being administered is temporarilyreduced; at the end of the drug holiday, dosing of the compound isresumed. The length of the drug holiday can vary from 2 days to 1 year.

In any of the aforementioned aspects involving the treatment ofproliferative disorders, including cancer, are further embodimentscomprising administering at least one additional agent selected from thegroup consisting of alemtuzumab, arsenic trioxide, asparaginase(pegylated or non-), bevacizumab, cetuximab, platinum-based compoundssuch as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin,irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate,Paclitaxel™, taxol, temozolomide, thioguanine, or classes of drugsincluding hormones (an antiestrogen, an antiandrogen, or gonadotropinreleasing hormone analogues, interferons such as alpha interferon,nitrogen mustards such as busulfan or melphalan or mechlorethamine,retinoids such as tretinoin, topoisomerase inhibitors such as irinotecanor topotecan, tyrosine kinase inhibitors such as gefinitinib orimatinib, or agents to treat signs or symptoms induced by such therapyincluding allopurinol, filgrastim, granisetron/ondansetron/palonosetron,dronabinol.

In any of the aforementioned aspects involving the prevention ortreatment of Btk-dependent or tyrosine kinase mediated diseases orconditions are further embodiments comprising identifying patients byscreening for a tyrosine kinase gene haplotype. In further oralternative embodiments the tyrosine kinase gene haplotype is a tyrosinekinase pathway gene, while in still further or alternative embodiments,the tyrosine kinase gene haplotype is a Btk haplotype.

In a further or alternative embodiments, the compounds of Formula (IA),(I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb) are reversibleinhibitors of Bruton's tyrosine kinase (Btk), while in still further oralternative embodiments, such reversible inhibitors are selective forBtk. In even further or alternative embodiments, such inhibitors have anIC₅₀ below 10 microM in enzyme assay. In one embodiment, a Btkreversible inhibitor has an IC₅₀ of less than 1 microM, and in anotherembodiment, less than 0.25 microM.

In further or alternative embodiments, the compounds of Formula (IA),(I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb) are selectivereversible inhibitors for Btk over Itk. In further or alternativeembodiments, the compounds of Formula (IA), (I), (Ia), (II), (III),(IV), (Va)-(Vh), or (VIa)-(VIb) are selective reversible inhibitors forBtk over Lck. In further or alternative embodiments, the compounds ofFormula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb)are selective reversible inhibitors for Btk over ABL. In further oralternative embodiments, the compounds of Formula (IA), (I), (Ia), (II),(III), (IV), (Va)-(Vh), or (VIa)-(VIb) are selective reversibleinhibitors for Btk over CMET. In further or alternative embodiments, thecompounds of Formula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or(VIa)-(VIb) are selective reversible inhibitors for Btk over EGFR. Infurther or alternative embodiments, the compounds of Formula (IA), (I),(Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb) are selectivereversible inhibitors for Btk over Lyn.

In further or alternative embodiments, the reversible Btk inhibitors arealso inhibitors of EGFR.

In a further or alternative embodiment, the compound of Formula (IA),Formula (I), Formula (Ia), Formula (II), Formula (III), Formula (IV),Formula (Va)-(Vh), or Formula (VIa)-(VIb), are irreversible inhibitorsof Bruton's tyrosine kinase (Btk), while in still further or alternativeembodiments, such irreversible inhibitors are selective for Btk. In evenfurther or alternative embodiments, such inhibitors have an IC₅₀ below10 microM in enzyme assay. In one embodiment, a Btk irreversibleinhibitor has an IC₅₀ of less than 1 microM, and in another embodiment,less than 0.25 microM.

In further or alternative embodiment, the compound of Formula (IA),Formula (I), Formula (Ia), Formula (II), Formula (III), Formula (IV),Formula (Va)-(Vh), or Formula (VIa)-(VIb) are selective irreversibleinhibitors for Btk over Itk. In further or alternative embodiment, thecompound of Formula (IA), Formula (I), Formula (Ia), Formula (II),Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb)are selective irreversible inhibitors for Btk over Lck. In further oralternative embodiment, the compound of Formula (IA), Formula (I),Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb) are selective irreversible inhibitorsfor Btk over ABL. In further or alternative embodiment, the compound ofFormula (IA), Formula (I), Formula (Ia), Formula (II), Formula (III),Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb) are selectiveirreversible inhibitors for Btk over CMET. In further or alternativeembodiment, the compound of Formula (IA), Formula (I), Formula (Ia),Formula (II), Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula(VIa)-(VIb), are selective irreversible inhibitors for Btk over EGFR. Infurther or alternative embodiment, the compound of Formula (IA), Formula(I), Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb), are selective irreversible inhibitorsfor Btk over Lyn.

In further or alternative embodiments, the irreversible Btk inhibitorsare also inhibitors of EGFR.

Other objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only, since variouschanges and modifications within the spirit and scope of the presentdisclosure will become apparent to those skilled in the art from thisdetailed description. The section headings used herein are fororganizational purposes only and are not to be construed as limiting thesubject matter described. All documents, or portions of documents, citedin the application including, but not limited to, patents, patentapplications, articles, books, manuals, and treatises are herebyexpressly incorporated by reference in their entirety for any purpose.

Certain Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. In the event that thereare a plurality of definitions for terms herein, those in this sectionprevail. Where reference is made to a URL or other such identifier oraddress, it is understood that such identifiers can change andparticular information on the internet can come and go, but equivalentinformation can be found by searching the internet. Reference theretoevidences the availability and public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, but not limited to, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference in their entirety for any purpose.

Definition of standard chemistry terms may be found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(T) H ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, proteinchemistry, biochemistry, recombinant DNA techniques and pharmacology,within the skill of the art are employed. Unless specific definitionsare provided, the nomenclature employed in connection with, and thelaboratory procedures and techniques of, analytical chemistry, syntheticorganic chemistry, and medicinal and pharmaceutical chemistry describedherein are those known in the art. Standard techniques can be used forchemical syntheses, chemical analyses, pharmaceutical preparation,formulation, and delivery, and treatment of patients. Standardtechniques can be used for recombinant DNA, oligonucleotide synthesis,and tissue culture and transformation (e.g., electroporation,lipofection). Reactions and purification techniques can be performede.g., using kits of manufacturer's specifications or as commonlyaccomplished in the art or as described herein. The foregoing techniquesand procedures can be generally performed of conventional methods wellknown in the art and as described in various general and more specificreferences that are cited and discussed throughout the presentspecification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods and compositions described herein,which will be limited only by the appended claims.

All publications and patents mentioned herein are incorporated herein byreference in their entirety for the purpose of describing anddisclosing, for example, the constructs and methodologies that aredescribed in the publications, which might be used in connection withthe methods, compositions and compounds described herein. Thepublications discussed herein are provided solely for their disclosureprior to the filing date of the present application. Nothing herein isto be construed as an admission that the inventors described herein arenot entitled to antedate such disclosure by virtue of prior invention orfor any other reason.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises five to fifteen carbon atoms (e.g.,C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five to eightcarbon atoms (e.g., C₅-C₈ alkyl). The alkyl is attached to the rest ofthe molecule by a single bond, for example, methyl (Me), ethyl (Et),n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.Unless stated otherwise specifically in the specification, an alkylgroup is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

The alkyl group could also be a “lower alkyl” having 1 to 6 carbonatoms.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x).

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to twelve carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Inother embodiments, an alkenyl comprises two to four carbon atoms. Thealkenyl is attached to the rest of the molecule by a single bond, forexample, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwisespecifically in the specification, an alkenyl group is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to twelve carbon atoms. Incertain embodiments, an alkynyl comprises two to eight carbon atoms. Inother embodiments, an alkynyl has two to four carbon atoms. The alkynylis attached to the rest of the molecule by a single bond, for example,ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unlessstated otherwise specifically in the specification, an alkynyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, for example,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a double bond or asingle bond and to the radical group through a double bond or a singlebond. The points of attachment of the alkenylene chain to the rest ofthe molecule and to the radical group can be through one carbon or anytwo carbons within the chain. Unless stated otherwise specifically inthe specification, an alkenylene chain is optionally substituted by oneor more of the following substituents: halo, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted unless otherwiseindicated.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from six to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. Aryl groupsinclude, but are not limited to, groups such as phenyl, fluorenyl, andnaphthyl. Unless stated otherwise specifically in the specification, theterm “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one ormore halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroarylor heteroarylalkyl, each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, benzyl, diphenylmethyland the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(c)-aryl, where R^(c)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl is optionally saturated,(i.e., containing single C—C bonds only) or unsaturated (i.e.,containing one or more double bonds or triple bonds.) A fully saturatedcarbocyclyl radical is also referred to as “cycloalkyl.” Examples ofmonocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturatedcarbocyclyl is also referred to as “cycloalkenyl.” Examples ofmonocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicalsinclude, for example, adamantyl, norbornyl (i.e.,bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwisestated specifically in the specification, the term “carbocyclyl” ismeant to include carbocyclyl radicals that are optionally substituted byone or more substituents independently selected from alkyl, alkenyl,alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcarbocyclyl, optionally substituted carbocyclylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —R^(b)—OR^(a), —R^(b)—SR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy”include alkyl, alkenyl, alkynyl and alkoxy structures in which at leastone hydrogen is replaced with a halogen atom. In certain embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are all the same as one another. In other embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are not all the same as one another.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical is optionally substituted as defined above for analkyl group.

As used herein, the term “non-aromatic heterocycle”, “heterocycloalkyl”or “heteroalicyclic” refers to a non-aromatic ring wherein one or moreatoms forming the ring is a heteroatom. A “non-aromatic heterocycle” or“heterocycloalkyl” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur. Theradicals may be fused with an aryl or heteroaryl. Heterocycloalkyl ringscan be formed by three, four, five, six, seven, eight, nine, or morethan nine atoms. Heterocycloalkyl rings can be optionally substituted.In certain embodiments, non-aromatic heterocycles contain one or morecarbonyl or thiocarbonyl groups such as, for example, oxo- andthio-containing groups. Examples of heterocycloalkyls include, but arenot limited to, lactams, lactones, cyclic imides, cyclic thioimides,cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran,piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane,piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane,isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone,thiazoline, thiazolidine, and 1,3-oxathiolane. Illustrative examples ofheterocycloalkyl groups, also referred to as non-aromatic heterocycles,include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Depending on the structure, aheterocycloalkyl group can be a monoradical or a diradical (i.e., aheterocycloalkylene group).

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises one to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) t-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—SR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O) N(R^(a))₂,—R^(b)—O—R—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R is an alkylene chain as defined above. If the heteroaryl is anitrogen-containing heteroaryl, the heteroaryl is optionally attached tothe alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Sulfanyl” refers to the —S— radical.

“Sulfinyl” refers to the —S(═O)— radical.

“Sulfonyl” refers to the —S(═O)₂— radical.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Imino” refers to the ═NH radical.

“Thioxo” refers to the ═S radical.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

An “aryloxy” group refers to an (aryl)O— group, where aryl is as definedherein.

“Cycloalkylalkyl” means an alkyl radical, as defined herein, substitutedwith a cycloalkyl group. Non-limiting cycloalkylalkyl groups includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, and the like.

As used herein, the terms “heteroalkyl” “heteroalkenyl” and“heteroalkynyl” include optionally substituted alkyl, alkenyl andalkynyl radicals in which one or more skeletal chain atoms is aheteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus orcombinations thereof. The heteroatom(s) may be placed at any interiorposition of the heteroalkyl group or at the position at which theheteroalkyl group is attached to the remainder of the molecule. Examplesinclude, but are not limited to, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃,—CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. In addition, up to two heteroatoms may beconsecutive, such as, by way of example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃.

The term “heteroatom” refers to an atom other than carbon or hydrogen.Heteroatoms are typically independently selected from among oxygen,sulfur, nitrogen, silicon and phosphorus, but are not limited to theseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms can all be the same as one another, or some orall of the two or more heteroatoms can each be different from theothers.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

An “isocyanato” group refers to a —NCO group.

An “isothiocyanato” group refers to a —NCS group.

The term “moiety” refers to a specific segment or functional group of amolecule.

Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

A “thioalkoxy” or “alkylthio” group refers to a —S-alkyl group.

A “alkylthioalkyl” group refers to an alkyl group substituted with a—S-alkyl group.

As used herein, the term “O-carboxy” or “acyloxy” refers to a group offormula RC(═O)O—.

“Carboxy” means a —C(O)OH radical.

As used herein, the term “acetyl” refers to a group of formula—C(═O)CH₃.

“Acyl” refers to the group —C(O)R.

As used herein, the term “trihalomethanesulfonyl” refers to a group offormula X₃CS(═O)₂— where X is a halogen.

“Cyanoalkyl” means an alkyl radical, as defined herein, substituted withat least one cyano group.

As used herein, the term “N-sulfonamido” or “sulfonylamino” refers to agroup of formula RS(═O)₂NH—.

As used herein, the term “O-carbamyl” refers to a group of formula—OC(═O)NR₂.

As used herein, the term “N-carbamyl” refers to a group of formulaROC(═O)NH—.

As used herein, the term “O-thiocarbamyl” refers to a group of formula—OC(═S)NR₂.

As used herein, “N-thiocarbamyl” refers to a group of formulaROC(═S)NH—.

As used herein, the term “C-amido” refers to a group of formula—C(═O)NR₂.

“Aminocarbonyl” refers to a —CONH₂ radical.

As used herein, the term “N-amido” refers to a group of formulaRC(═O)NH—.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andnon-aromatic heterocycle (bonded through a ring carbon).

“Hydroxyalkyl” refers to an alkyl radical, as defined herein,substituted with at least one hydroxy group. Non-limiting examples of ahydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl.

“Alkoxyalkyl” refers to an alkyl radical, as defined herein, substitutedwith an alkoxy group, as defined herein.

An “alkenyloxy” group refers to a (alkenyl)O— group, where alkenyl is asdefined herein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where xand y are selected from among x=1, y=1 and x=2, y=0. When x=2, the alkylgroups, taken together with the N atom to which they are attached, canoptionally form a cyclic ring system.

“Alkylaminoalkyl” refers to an alkyl radical, as defined herein,substituted with an alkylamine, as defined herein.

An “amide” is a chemical moiety with the formula —C(O)NHR or —NHC(O)R,where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon) and heteroalicyclic (bonded through aring carbon). An amide moiety may form a linkage between an amino acidor a peptide molecule and a compound described herein, thereby forming aprodrug. Any amine, or carboxyl side chain on the compounds describedherein can be amidified. The procedures and specific groups to make suchamides are known to those of skill in the art and can readily be foundin reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from among alkyl, cycloalkyl, aryl, heteroaryl (bondedthrough a ring carbon) and heteroalicyclic (bonded through a ringcarbon). Any hydroxy, or carboxyl side chain on the compounds describedherein can be esterified. The procedures and specific groups to makesuch esters are known to those of skill in the art and can readily befound in reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

As used herein, the term “ring” refers to any covalently closedstructure. Rings include, for example, carbocycles (e.g., aryls andcycloalkyls), heterocycles (e.g., heteroaryls and non-aromaticheterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics(e.g., cycloalkyls and non-aromatic heterocycles). Rings can beoptionally substituted. Rings can be monocyclic or polycyclic.

As used herein, the term “ring system” refers to one, or more than onering.

The term “membered ring” can embrace any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridine, pyran andthiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, andthiophene are 5-membered rings.

The term “fused” refers to structures in which two or more rings shareone or more bonds.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,cyano, halo, acyl, nitro, haloalkyl, fluoroalkyl, haloalkoxy, amino,including mono- and di-substituted amino groups, and the N-oxide andprotected derivatives thereof; or “optionally substituted” or“substituted” may be -L_(s)R_(s), wherein each L_(s) is independentlyselected from a bond, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O)₂—, —NH—,—N(CH₃)—, —NHC(O)—, —N(CH₃)C(O)—, —C(O)NH—, —C(O)N(CH₃)—, S(═O)₂NH—,—NHS(═O)₂, —OC(O)NH—, —NHC(O)O—, -(substituted or unsubstituted C₁-C₆alkyl)-, or -(substituted or unsubstituted C₂-C₆ alkenyl)-; and eachR_(s) is independently selected from H, C₁-C₆alkyl, C₂-C₆ alkenyl,C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, heteroaryl, or heteroalkyl. Theprotecting groups that may form the protective derivatives of the abovesubstituents are known to those of skill in the art and may be found inreferences such as Greene and Wuts, above.

The term “nucleophile” or “nucleophilic” refers to an electron richcompound, or moiety thereof. An example of a nucleophile includes, butin no way is limited to, a cysteine residue of a molecule, such as, forexample Cys 481 of Btk.

The term “electrophile”, or “electrophilic” refers to an electron pooror electron deficient molecule, or moiety thereof. Examples ofelectrophiles include, but in no way are limited to, Micheal acceptormoieties.

The term “acceptable” or “pharmaceutically acceptable”, with respect toa formulation, composition or ingredient, as used herein, means havingno persistent detrimental effect on the general health of the subjectbeing treated or does not abrogate the biological activity or propertiesof the compound, and is relatively nontoxic.

As used herein, the term “agonist” refers to a compound, the presence ofwhich results in a biological activity of a protein that is the same asthe biological activity resulting from the presence of a naturallyoccurring ligand for the protein, such as, for example, Btk.

As used herein, the term “partial agonist” refers to a compound thepresence of which results in a biological activity of a protein that isof the same type as that resulting from the presence of a naturallyoccurring ligand for the protein, but of a lower magnitude.

As used herein, the term “antagonist” refers to a compound, the presenceof which results in a decrease in the magnitude of a biological activityof a protein. In certain embodiments, the presence of an antagonistresults in complete inhibition of a biological activity of a protein,such as, for example, Btk. In certain embodiments, an antagonist is aninhibitor.

As used herein, “amelioration” of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

“Bioavailability” refers to the percentage of the weight of compoundsdisclosed herein, such as, compounds of any of Formula (IA), Formula(I), Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb), dosed that is delivered into thegeneral circulation of the animal or human being studied. The totalexposure (AUC_((0-∞))) of a drug when administered intravenously isusually defined as 100% bioavailable (F %). “Oral bioavailability”refers to the extent to which compounds disclosed herein, such as,compounds of any of Formula (IA), Formula (I), Formula (Ia), Formula(II), Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula(VIa)-(VIb), are absorbed into the general circulation when thepharmaceutical composition is taken orally as compared to intravenousinjection.

“Blood plasma concentration” refers to the concentration of compoundsdisclosed herein, such as, compounds of any of Formula (IA), Formula(I), Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb), in the plasma component of blood of asubject. It is understood that the plasma concentration of compounds ofany of Formula (IA), Formula (I), Formula (Ia), Formula (II), Formula(III), Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb), may varysignificantly between subjects, due to variability with respect tometabolism and/or possible interactions with other therapeutic agents.In accordance with one embodiment disclosed herein, the blood plasmaconcentration of the compounds of any of Formula (IA), Formula (I),Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb), may vary from subject to subject.Likewise, values such as maximum plasma concentration (C_(max)) or timeto reach maximum plasma concentration (T_(max)), or total area under theplasma concentration time curve (AUC_((0-∞))) may vary from subject tosubject. Due to this variability, the amount necessary to constitute “atherapeutically effective amount” of a compound of any of Formula (IA),Formula (I), Formula (Ia), Formula (II), Formula (III), Formula (IV),Formula (Va)-(Vh), or Formula (VIa)-(VIb), may vary from subject tosubject.

The term “Bruton's tyrosine kinase,” as used herein, refers to Bruton'styrosine kinase from Homo sapiens, as disclosed in, e.g., U.S. Pat. No.6,326,469 (GenBank Accession No. NP_000052).

The term “Bruton's tyrosine kinase homolog,” as used herein, refers toorthologs of Bruton's tyrosine kinase, e.g., the orthologs from mouse(GenBank Acession No. AAB47246), dog (GenBank Acession No. XP_549139.),rat (GenBank Acession No. NP_001007799), chicken (GenBank Acession No.NP_989564), or zebra fish (GenBank Acession No. XP_698117), and fusionproteins of any of the foregoing that exhibit kinase activity towardsone or more substrates of Bruton's tyrosine kinase (e.g. a peptidesubstrate having the amino acid sequence “AVLESEEELYSSARQ” (SEQ ID NO:1)).

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition including a compound as disclosed herein required to providea clinically significant decrease in disease symptoms without undueadverse side effects. An appropriate “effective amount” in anyindividual case may be determined using techniques, such as a doseescalation study. The term “therapeutically effective amount” includes,for example, a prophylactically effective amount. An “effective amount”of a compound disclosed herein is an amount effective to achieve adesired pharmacologic effect or therapeutic improvement without undueadverse side effects. It is understood that “an effect amount” or “atherapeutically effective amount” can vary from subject to subject, dueto variation in metabolism of the compound of any of Formula (IA),Formula (I), Formula (Ia), Formula (II), Formula (III), Formula (IV),Formula (Va)-(Vh), or Formula (VIa)-(VIb), age, weight, generalcondition of the subject, the condition being treated, the severity ofthe condition being treated, and the judgment of the prescribingphysician. By way of example only, therapeutically effective amounts maybe determined by routine experimentation, including but not limited to adose escalation clinical trial.

The terms “enhance” or “enhancing” means to increase or prolong eitherin potency or duration a desired effect. By way of example, “enhancing”the effect of therapeutic agents refers to the ability to increase orprolong, either in potency or duration, the effect of therapeutic agentson during treatment of a disease, disorder or condition. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of a therapeutic agent in the treatmentof a disease, disorder or condition. When used in a patient, amountseffective for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

The term “homologous cysteine,” as used herein refers to a cysteineresidue found with in a sequence position that is homologous to that ofcysteine 481 of Bruton's tyrosine kinase, as defined herein. Forexample, cysteine 482 is the homologous cysteine of the rat ortholog ofBruton's tyrosine kinase; cysteine 479 is the homologous cysteine of thechicken ortholog; and cysteine 481 is the homologous cysteine in thezebra fish ortholog. In another example, the homologous cysteine of TXK,a Tec kinase family member related to Bruton's tyrosine, is Cys 350.

The term “identical,” as used herein, refers to two or more sequences orsubsequences which are the same. In addition, the term “substantiallyidentical,” as used herein, refers to two or more sequences which have apercentage of sequential units which are the same when compared andaligned for maximum correspondence over a comparison window, ordesignated region as measured using comparison algorithms or by manualalignment and visual inspection. By way of example only, two or moresequences may be “substantially identical” if the sequential units areabout 60% identical, about 65% identical, about 70% identical, about 75%identical, about 80% identical, about 85% identical, about 90%identical, or about 95% identical over a specified region. Suchpercentages to describe the “percent identity” of two or more sequences.The identity of a sequence can exist over a region that is at leastabout 75-100 sequential units in length, over a region that is about 50sequential units in length, or, where not specified, across the entiresequence. This definition also refers to the complement of a testsequence. By way of example only, two or more polypeptide sequences areidentical when the amino acid residues are the same, while two or morepolypeptide sequences are “substantially identical” if the amino acidresidues are about 60% identical, about 65% identical, about 70%identical, about 75% identical, about 80% identical, about 85%identical, about 90% identical, or about 95% identical over a specifiedregion. The identity can exist over a region that is at least about75-100 amino acids in length, over a region that is about 50 amino acidsin length, or, where not specified, across the entire sequence of apolypeptide sequence. In addition, by way of example only, two or morepolynucleotide sequences are identical when the nucleic acid residuesare the same, while two or more polynucleotide sequences are“substantially identical” if the nucleic acid residues are about 60%identical, about 65% identical, about 70% identical, about 75%identical, about 80% identical, about 85% identical, about 90%identical, or about 95% identical over a specified region. The identitycan exist over a region that is at least about 75-100 nucleic acids inlength, over a region that is about 50 nucleic acids in length, or,where not specified, across the entire sequence of a polynucleotidesequence.

The terms “inhibits”, “inhibiting”, or “inhibitor” of a kinase, as usedherein, refer to inhibition of enzymatic phosphotransferase activity.

The term “irreversible inhibitor,” as used herein, refers to a compoundthat, upon contact with a target protein (e.g., a kinase) causes theformation of a new covalent bond with or within the protein, whereby oneor more of the target protein's biological activities (e.g.,phosphotransferase activity) is diminished or abolished notwithstandingthe subsequent presence or absence of the irreversible inhibitor. Incontrast, a reversible inhibitor compound upon contact with a targetprotein does not cause the formation of a new covalent bond with orwithin the protein and therefore can associate and dissociate from thetarget protein.

The term “irreversible Btk inhibitor,” as used herein, refers to aninhibitor of Btk that can form a covalent bond with an amino acidresidue of Btk. In one embodiment, the irreversible inhibitor of Btk canform a covalent bond with a Cys residue of Btk; in particularembodiments, the irreversible inhibitor can form a covalent bond with aCys 481 residue (or a homolog thereof) of Btk or a cysteine residue inthe homologous corresponding position of another tyrosine kinase.

The term “isolated,” as used herein, refers to separating and removing acomponent of interest from components not of interest. Isolatedsubstances can be in either a dry or semi-dry state, or in solution,including but not limited to an aqueous solution. The isolated componentcan be in a homogeneous state or the isolated component can be a part ofa pharmaceutical composition that comprises additional pharmaceuticallyacceptable carriers and/or excipients. By way of example only, nucleicacids or proteins are “isolated” when such nucleic acids or proteins arefree of at least some of the cellular components with which it isassociated in the natural state, or that the nucleic acid or protein hasbeen concentrated to a level greater than the concentration of its invivo or in vitro production. Also, by way of example, a gene is isolatedwhen separated from open reading frames which flank the gene and encodea protein other than the gene of interest.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes, such as, oxidation reactions) by which aparticular substance is changed by an organism. Thus, enzymes mayproduce specific structural alterations to a compound. For example,cytochrome P450 catalyzes a variety of oxidative and reductive reactionswhile uridine diphosphate glucuronyl transferases catalyze the transferof an activated glucuronic-acid molecule to aromatic alcohols, aliphaticalcohols, carboxylic acids, amines and free sulfhydryl groups. Furtherinformation on metabolism may be obtained from The Pharmacological Basisof Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of thecompounds disclosed herein can be identified either by administration ofcompounds to a host and analysis of tissue samples from the host, or byincubation of compounds with hepatic cells in vitro and analysis of theresulting compounds. Both methods are well known in the art. In someembodiments, metabolites of a compound are formed by oxidative processesand correspond to the corresponding hydroxy-containing compound. In someembodiments, a compound is metabolized to pharmacologically activemetabolites.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator can cause an increaseor decrease in the magnitude of a certain activity of a moleculecompared to the magnitude of the activity in the absence of themodulator. In certain embodiments, a modulator is an inhibitor, whichdecreases the magnitude of one or more activities of a molecule. Incertain embodiments, an inhibitor completely prevents one or moreactivities of a molecule. In certain embodiments, a modulator is anactivator, which increases the magnitude of at least one activity of amolecule. In certain embodiments the presence of a modulator results inan activity that does not occur in the absence of the modulator.

The term “prophylactically effective amount,” as used herein, refersthat amount of a composition applied to a patient which will relieve tosome extent one or more of the symptoms of a disease, condition ordisorder being treated. In such prophylactic applications, such amountsmay depend on the patient's state of health, weight, and the like. It isconsidered well within the skill of the art for one to determine suchprophylactically effective amounts by routine experimentation,including, but not limited to, a dose escalation clinical trial.

As used herein, the term “selective binding compound” refers to acompound that selectively binds to any portion of one or more targetproteins.

As used herein, the term “selectively binds” refers to the ability of aselective binding compound to bind to a target protein, such as, forexample, Btk, with greater affinity than it binds to a non-targetprotein. In certain embodiments, specific binding refers to binding to atarget with an affinity that is at least 10, 50, 100, 250, 500, 1000 ormore times greater than the affinity for a non-target.

As used herein, the term “selective modulator” refers to a compound thatselectively modulates a target activity relative to a non-targetactivity. In certain embodiments, specific modulater refers tomodulating a target activity at least 10, 50, 100, 250, 500, 1000 timesmore than a non-target activity.

The term “substantially purified,” as used herein, refers to a componentof interest that may be substantially or essentially free of othercomponents which normally accompany or interact with the component ofinterest prior to purification. By way of example only, a component ofinterest may be “substantially purified” when the preparation of thecomponent of interest contains less than about 30%, less than about 25%,less than about 20%, less than about 15%, less than about 10%, less thanabout 5%, less than about 4%, less than about 3%, less than about 2%, orless than about 1% (by dry weight) of contaminating components. Thus, a“substantially purified” component of interest may have a purity levelof about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,about 96%, about 97%, about 98%, about 99% or greater.

The term “subject” as used herein, refers to an animal which is theobject of treatment, observation or experiment. By way of example only,a subject may be, but is not limited to, a mammal including, but notlimited to, a human.

As used herein, the term “target activity” refers to a biologicalactivity capable of being modulated by a selective modulator. Certainexemplary target activities include, but are not limited to, bindingaffinity, signal transduction, enzymatic activity, tumor growth,inflammation or inflammation-related processes, and amelioration of oneor more symptoms associated with a disease or condition.

As used herein, the term “target protein” refers to a molecule or aportion of a protein capable of being bound by a selective bindingcompound. In certain embodiments, a target protein is Btk.

The terms “treat,” “treating” or “treatment”, as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition. The terms “treat,”“treating” or “treatment”, include, but are not limited to, prophylacticand/or therapeutic treatments.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as inhibition of Btk, in an assay that measures suchresponse.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

DETAILED DESCRIPTION OF THE INVENTION

The methods described herein include administering to a subject in needa composition containing a therapeutically effective amount of one ormore reversible or irreversible Btk inhibitor compounds describedherein. Without being bound by theory, the diverse roles played by Btksignaling in various hematopoietic cell functions, e.g., B-cell receptoractivation, suggests that small molecule Btk inhibitors are useful forreducing the risk of or treating a variety of diseases affected by oraffecting many cell types of the hematopoetic lineage including, e.g.,autoimmune diseases, heteroimmune conditions or diseases, inflammatorydiseases, cancer (e.g., B-cell proliferative disorders), andthromboembolic disorders. Further, the irreversible Btk inhibitorcompounds described herein can be used to inhibit a small subset ofother tyrosine kinases that share homology with Btk by having a cysteineresidue (including a Cys 481 residue) that can form a covalent bond withthe irreversible inhibitor. Thus, a subset of tyrosine kinases otherthan Btk are also expected to be useful as therapeutic targets in anumber of health conditions.

In some embodiments, the methods described herein can be used to treatan autoimmune disease, which includes, but is not limited to, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barré syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis. Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behçet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, and vulvodynia.

In some embodiments, the methods described herein can be used to treatheteroimmune conditions or diseases, which include, but are not limitedto graft versus host disease, transplantation, transfusion, anaphylaxis,allergies (e.g., allergies to plant pollens, latex, drugs, foods, insectpoisons, animal hair, animal dander, dust mites, or cockroach calyx),type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, andatopic dermatitis.

In further embodiments, the methods described herein can be used totreat an inflammatory disease, which includes, but is not limited toasthma, inflammatory bowel disease, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

In yet other embodiments, the methods described herein can be used totreat a cancer, e.g., B-cell proliferative disorders, which include, butare not limited to diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cellprolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrommacroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma,plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginalzone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large Bcell lymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

In further embodiments, the methods described herein can be used totreat thromboembolic disorders, which include, but are not limited tomyocardial infarct, angina pectoris (including unstable angina),reocclusions or restenoses after angioplasty or aortocoronary bypass,stroke, transitory ischemia, peripheral arterial occlusive disorders,pulmonary embolisms, and deep venous thromboses.

Symptoms, diagnostic tests, and prognostic tests for each of theabove-mentioned conditions are known in the art. See, e.g., Harrison'sPrinciples of Internal Medicine©,” 16th ed., 2004, The McGraw-HillCompanies, Inc. Dey et al. (2006), Cytojournal 3(24), and the “RevisedEuropean American Lymphoma” (REAL) classification system (see, e.g., thewebsite maintained by the National Cancer Institute).

A number of animal models of are useful for establishing a range oftherapeutically effective doses of reversible or irreversible Btkinhibitor compounds for treating any of the foregoing diseases.

For example, dosing of reversible or irreversible Btk inhibitorcompounds for treating an autoimmune disease can be assessed in a mousemodel of rheumatoid arthitis. In this model, arthritis is induced inBalb/c mice by administering anti-collagen antibodies andlipopolysaccharide. See Nandakumar et al. (2003), Am. J. Pathol163:1827-1837.

In another example, dosing of reversible or irreversible Btk inhibitorsfor the treatment of B-cell proliferative disorders can be examined in,e.g., a human-to-mouse xenograft model in which human B-cell lymphomacells (e.g. Ramos cells) are implanted into immunodefficient mice (e.g.,“nude” mice) as described in, e.g., Pagel et al. (2005), Clin Cancer Res11(13):4857-4866.

Animal models for treatment of thromboembolic disorders are also known.

The therapeutic efficacy of the compound for one of the foregoingdiseases can be optimized during a course of treatment. For example, asubject being treated can undergo a diagnostic evaluation to correlatethe relief of disease symptoms or pathologies to inhibition of in vivoBtk activity achieved by administering a given dose of an irreversibleBtk inhibitor. Cellular assays known in the art can be used to determinein vivo activity of Btk in the presence or absence of an irreversibleBtk inhibitor. For example, since activated Btk is phosphorylated attyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specificimmunocytochemical staining of P-Y223 or P-Y551-positive cells can beused to detect or quantify activation of Bkt in a population of cells(e.g., by FACS analysis of stained vs unstained cells). See, e.g.,Nisitani et al. (1999), Proc. Natl. Acad. Sci, USA 96:2221-2226. Thus,the amount of the Btk inhibitor compound that is administered to asubject can be increased or decreased as needed so as to maintain alevel of Btk inhibition optimal for treating the subject's diseasestate.

Compounds

In the following description of reversible or irreversible Btk compoundssuitable for use in the methods described herein, definitions ofreferred-to standard chemistry terms may be found in reference works (ifnot otherwise defined herein), including Carey and Sundberg “AdvancedOrganic Chemistry 4th Ed.” Vols. A (2000) and B (2001), Plenum Press,New York. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology, within the ordinary skill of the artare employed. In addition, nucleic acid and amino acid sequences for Btk(e.g., human Btk) are known in the art as disclosed in, e.g., U.S. Pat.No. 6,326,469. Unless specific definitions are provided, thenomenclature employed in connection with, and the laboratory proceduresand techniques of, analytical chemistry, synthetic organic chemistry,and medicinal and pharmaceutical chemistry described herein are thoseknown in the art. Standard techniques can be used for chemicalsyntheses, chemical analyses, pharmaceutical preparation, formulation,and delivery, and treatment of patients.

The Btk inhibitor compounds described herein are selective for Btk andkinases having a cysteine residue in an amino acid sequence position ofthe tyrosine kinase that is homologous to the amino acid sequenceposition of cysteine 481 in Btk. Inhibitor compounds described hereininclude a Michael acceptor moiety.

Generally, a reversible or irreversible inhibitor compound of Btk usedin the methods described herein is identified or characterized in an invitro assay, e.g., an acellular biochemical assay or a cellularfunctional assay. Such assays are useful to determine an in vitro IC₅₀for a reversible or irreversible Btk inhibitor compound.

For example, an acellular kinase assay can be used to determine Btkactivity after incubation of the kinase in the absence or presence of arange of concentrations of a candidate irreversible Btk inhibitorcompound. If the candidate compound is in fact an irreversible Btkinhibitor, Btk kinase activity will not be recovered by repeat washingwith inhibitor-free medium. See, e.g., J. B. Smaill, et al. (1999), J.Med. Chem. 42(10):1803-1815. Further, covalent complex formation betweenBtk and a candidate irreversible Btk inhibitor is a useful indicator ofirreversible inhibition of Btk that can be readily determined by anumber of methods known in the art (e.g., mass spectrometry). Forexample, some irreversible Btk-inhibitor compounds can form a covalentbond with Cys 481 of Btk (e.g., via a Michael reaction).

Cellular functional assays for Btk inhibition include measuring one ormore cellular endpoints in response to stimulating a Btk-mediatedpathway in a cell line (e.g., BCR activation in Ramos cells) in theabsence or presence of a range of concentrations of a candidateirreversible Btk inhibitor compound. Useful endpoints for determining aresponse to BCR activation include, e.g., autophosphorylation of Btk,phosphorylation of a Btk target protein (e.g., PLC-γ), and cytoplasmiccalcium flux.

High throughput assays for many acellular biochemical assays (e.g.,kinase assays) and cellular functional assays (e.g., calcium flux) arewell known to those of ordinary skill in the art. In addition, highthroughput screening systems are commercially available (see, e.g.,Zymark Corp., Hopkinton, Mass.; Air Technical Industries, Mentor, Ohio;Beckman Instruments, Inc. Fullerton, Calif.; Precision Systems, Inc.,Natick, Mass., etc.). These systems typically automate entire proceduresincluding all sample and reagent pipetting, liquid dispensing, timedincubations, and final readings of the microplate in detector(s)appropriate for the assay. Automated systems thereby allow theidentification and characterization of a large number of reversible orirreversible Btk compounds without undue effort.

Reversible or irreversible Btk inhibitor compounds can be used for themanufacture of a medicament for treating any of the foregoing conditions(e.g., autoimmune diseases, inflammatory diseases, allergy disorders,B-cell proliferative disorders, or thromboembolic disorders).

In some embodiments, the reversible or irreversible Btk inhibitorcompound used for the methods described herein inhibits Btk or a Btkhomolog kinase activity with an in vitro IC₅₀ of less than about 10 μM.(e.g., less than about 1 μM, less than about 0.5 μM, less than about 0.4μM, less than about 0.3 μM, less than about 0.1, less than about 0.08μM, less than about 0.06 μM, less than about 0.05 μM, less than about0.04 μM, less than about 0.03 μM, less than about 0.02 μM, less thanabout 0.01, less than about 0.008 μM, less than about 0.006 μM, lessthan about 0.005 μM, less than about 0.004 μM, less than about 0.003 μM,less than about 0.002 μM, less than about 0.001, less than about 0.00099μM, less than about 0.00098 μM, less than about 0.00097 μM, less thanabout 0.00096 μM, less than about 0.00095 μM, less than about 0.00094μM, less than about 0.00093 μM, less than about 0.00092, or less thanabout 0.00090 μM).

In one embodiment, the irreversible Btk inhibitor compound selectivelyand irreversibly inhibits an activated form of its target tyrosinekinase (e.g., a phosphorylated form of the tyrosine kinase). Forexample, activated Btk is transphosphorylated at tyrosine 551. Thus, inthese embodiments the irreversible Btk inhibitor inhibits the targetkinase in cells only once the target kinase is activated by thesignaling events.

Described herein are compounds of any of Formula (IA), Formula (I),Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb). Also described herein arepharmaceutically acceptable salts, pharmaceutically acceptable solvates,pharmaceutically active metabolites, and pharmaceutically acceptableprodrugs of such compounds. Pharmaceutical compositions that include atleast one such compound or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, pharmaceutically active metaboliteor pharmaceutically acceptable prodrug of such compound, are provided.In some embodiments, when compounds disclosed herein contain anoxidizable nitrogen atom, the nitrogen atom can be converted to anN-oxide by methods well known in the art. In certain embodiments,isomers and chemically protected forms of compounds having a structurerepresented by any of Formula (IA), Formula (I), Formula (Ia), Formula(II), Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula(VIa)-(VIb) are also provided.

In another embodiment are compounds having the structure of Formula(IA):

wherein:

ring A is substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;

W is —C(R₂)— or —N—; X is —C(R₂)— or —N—;

Y is optionally present and when present is —CH₂O—, —OCH₂—, —OCH₂CH₂O—,—O—, —N(R₃)—, —C(O)—, —N(R₃)C(O)—, —C(O)N(R₃)—, —N(R₃)C(O)N(R₃)—,—S(O)—, —S(O)₂—, —N(R₃)S(O)₂—, —S(O)₂N(R₃)—, —C(═NH)—, —C(═NH)N(R₃)—,—C(═NH)N(R₃)—, or substituted or unsubstituted C₁-C₄alkylene; Z isoptionally present and when present is substituted or unsubstitutedC₁-C₃alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;

G is

R₁ is —R₄, —CH₂R₄, —C(O)R₉, —C(O)C(O)R₉, —C(O)OR₄, —C(O)N(R₃)(R₄), or—S(O)₂R₉;R_(1′) is —C(O)R_(9′), —C(O)C(O)R₉, —C(O)OR₄, —C(O)N(R₃)(R₄), or—S(O)₂R₉;each R₂ is independently H, substituted or unsubstituted C₁-C₄alkyl,—CN, or halogen;each R₃ is independently is H, or substituted or unsubstitutedC₁-C₄alkyl;each R₄ is independently H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;R₅ is H, substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl; or R₁ and R₅ togetherwith the nitrogen atom to which they are attached are combined to form asubstituted or unsubstituted C₂-C₉heterocycloalkyl ring;each R₆ is independently halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂; or R₁ and R₆ arecombined to form a substituted or unsubstituted C₂-C₉heterocycloalkylring;each R₇ is independently halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂;R₉ is —R₄, or

R₁₀ is H, halogen, —CN, or -L₁-L₂;R₁₁ and R₁₂ are independently H, halogen, —CN, or -L₁-L₂; or R₁₁ and R₁₂taken together form a bond;each L₁ is optionally present and when present each L₁ is independentlysubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂aryl, substituted or unsubstituted C₁-C₁₂heteroaryl,—C(═O)—, —O—, or —S—;each L₂ is independently H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl,substituted or unsubstituted C₁-C₁₂heteroaryl or —N(R₁₃)₂;each R₁₃ is independently H, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₂-C₇ heterocycloalkyl, C₆-C₁₂aryl, orC₁-C₁₂heteroaryl;n is 0-3;p is 0-3; andq is 0-3;or a pharmaceutically acceptable solvate, pharmaceutically acceptablesalt, or pharmaceutically acceptable prodrug thereof;provided thati) when W is N, and R₁ is H, t-Boc, or —C(O)—CH═CH₂; then X is otherthan C-Et or N; andii) when W is N, G is

then X is CH or N;iii) when W is N, and X is CH; then R_(1′) is other than —C(O)Me, ort-Boc; andiv) when n is 0; then each of p and q is independently 0, 1, or 2.

In one embodiment, each R₂ is independently H, —CN, or halogen.

In another embodiment, each of W and X is N. In another embodiment, eachof W and X is N, ring A is phenyl, Y is —C(O)—, and Z is morpholinyl.

In another embodiment, each of W and X is N, and R_(1′) is —C(O)R_(9′),—C(O)C(O)R₉, —C(O)OR₄, —C(O)N(R₃)(R₄), or —S(O)₂R₉.

In another embodiment, each of W and X is N, and R_(1′) is —C(O)R_(9′),—C(O)OR₄, —C(O)N(R₃)(R₄), or —S(O)₂R₉.

In another embodiment, X is CH.

In another embodiment, W is N, X is CH, and R_(1′) is —C(O)R_(9′),—C(O)C(O)R₉, —C(O)OR₄, —C(O)N(R₃)(R₄), or —S(O)₂R₉.

In another embodiment, W is N, X is CH, and R_(1′) is —C(O)R_(9′),—C(O)OR₄, —C(O)N(R₃)(R₄), or —S(O)₂R₉.

In another embodiment are compounds having the structure of Formula (I):

wherein:

ring A is substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;

W is —C(R₂)— or —N—; X is —C(R₂)— or —N—;

Y is optionally present and when present is —CH₂O—, —OCH₂—, —OCH₂CH₂O—,—O—, —N(R₃)—, —C(O)—, —N(R₃)C(O)—, —C(O)N(R₃)—, —N(R₃)C(O)N(R₃)—,—S(O)—, —S(O)₂—, —N(R₃)S(O)₂—, —S(O)₂N(R₃)—, —C(═NH)—, —C(═NH)N(R₃)—, orsubstituted or unsubstituted C₁-C₄alkylene;Z is optionally present and when present is substituted or unsubstitutedC₁-C₃alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;

G is

R₁ is —R₄, —CH₂R₄, —C(O)R₉, —C(O)C(O)R₉, —C(O)OR₄, —C(O)N(R₃)(R₄), or—S(O)₂R₉;each R₂ is independently H, —CN, or halogen;each R₃ is independently is H, or substituted or unsubstitutedC₁-C₄alkyl;each R₄ is independently H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;R₅ is H, substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl; or R₁ and R₅ togetherwith the nitrogen atom to which they are attached are combined to form asubstituted or unsubstituted C₂-C₉heterocycloalkyl ring;each R₆ is independently halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂; or R₁ and R₆ arecombined to form a substituted or unsubstituted C₂-C₉heterocycloalkylring;each R₇ is independently halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂;R₉ is —R₄, or

R₁₀ is H, halogen, —CN, or -L₁-L₂;R₁₁ and R₁₂ are independently H, halogen, —CN, or -L₁-L₂; or R₁₁ and R₁₂taken together form a bond;each L₁ is optionally present and when present each L₁ is independentlysubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂aryl, substituted or unsubstituted C₁-C₁₂heteroaryl,—C(═O)—, —O—, or —S—;each L₂ is independently H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl,substituted or unsubstituted C₁-C₁₂heteroaryl or —N(R₁₃)₂;each R₁₃ is independently H, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₂-C₇ heterocycloalkyl, C₆-C₁₂aryl, orC₁-C₁₂heteroaryl;p is 0-3; andq is 0-3;or a pharmaceutically acceptable solvate, pharmaceutically acceptablesalt, or pharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (IA) or (I) wherein Formula(IA) or (I) wherein ring A is substituted or unsubstitutedC₃-C₆cycloalkyl. In another embodiment is a compound of Formula (IA) or(I) wherein Formula (IA) or (I) wherein ring A is substituted orunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (IA) or (I) wherein Formula (IA) or (I) wherein ring A issubstituted or unsubstituted C₆-C₁₂aryl. In another embodiment is acompound of Formula (IA) or (I) wherein Formula (IA) or (I) wherein ringA is substituted or unsubstituted C₁-C₁₂heteroaryl.

In another embodiment is a compound of Formula (IA) or (I) whereinFormula (IA) or (I) wherein ring A is substituted or unsubstitutedphenyl. In another embodiment is a compound of Formula (IA) or (I)wherein Formula (IA) or (I) wherein ring A is substituted orunsubstituted phenyl, Y is absent, and Z is substituted or unsubstitutedC₁-C₃alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl. In anotherembodiment is a compound of Formula (IA) or (I) wherein Formula (IA) or(I) wherein ring A is substituted or unsubstituted phenyl, Y is absent,and Z is substituted or unsubstituted C₁-C₃alkyl. In another embodimentis a compound of Formula (IA) or (I) wherein Formula (IA) or (I) whereinring A is substituted or unsubstituted phenyl, Y is absent, and Z issubstituted or unsubstituted C₃-C₆cycloalkyl. In another embodiment is acompound of Formula (IA) or (I) wherein Formula (IA) or (I) wherein ringA is substituted or unsubstituted phenyl, Y is absent, and Z issubstituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (IA) or (I) wherein Formula (IA) or(I) wherein ring A is substituted or unsubstituted phenyl, Y is absent,and Z is substituted or unsubstituted C₆-C₁₂aryl. In another embodimentis a compound of Formula (IA) or (I) wherein Formula (IA) or (I) whereinring A is substituted or unsubstituted phenyl, Y is absent, and Z issubstituted or unsubstituted C₁-C₁₂heteroaryl. In another embodiment isa compound of Formula (IA) or (I) wherein Formula (IA) or (I) whereinring A is substituted or unsubstituted phenyl, Y is absent, and Z is asubstituted or unsubstituted pyrimidine. In another embodiment is acompound of Formula (IA) or (I) wherein Formula (IA) or (I) wherein ringA is substituted or unsubstituted phenyl, Y is absent, and Z is asubstituted or unsubstituted oxazole.

In another embodiment is a compound of Formula (IA) or (I) whereinFormula (IA) or (I) wherein ring A is substituted or unsubstitutedphenyl, Y is —C(O)—, and Z is substituted or unsubstituted C₁-C₃alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl. In anotherembodiment is a compound of Formula (IA) or (I) wherein Formula (IA) or(I) wherein ring A is substituted or unsubstituted phenyl, Y is —C(O)—,and Z is substituted or unsubstituted C₁-C₃alkyl. In another embodimentis a compound of Formula (IA) or (I) wherein Formula (IA) or (I) whereinring A is substituted or unsubstituted phenyl, Y is —C(O)—, and Z issubstituted or unsubstituted C₃-C₆cycloalkyl. In another embodiment is acompound of Formula (IA) or (I) wherein Formula (IA) or (I) wherein ringA is substituted or unsubstituted phenyl, Y is —C(O)—, and Z issubstituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (IA) or (I) wherein Formula (IA) or(I) wherein ring A is substituted or unsubstituted phenyl, Y is —C(O)—,and Z is substituted or unsubstituted morpholine. In another embodimentis a compound of Formula (IA) or (I) wherein Formula (IA) or (I) whereinring A is substituted or unsubstituted phenyl, Y is —C(O)—, and Z issubstituted or unsubstituted C₆-C₁₂aryl. In another embodiment is acompound of Formula (IA) or (I) wherein Formula (IA) or (I) wherein ringA is substituted or unsubstituted phenyl, Y is —C(O)—, and Z issubstituted or unsubstituted C₁-C₁₂heteroaryl.

In another embodiment is a compound of Formula (IA) or (I) whereinFormula (IA) or (I) wherein G is

In another embodiment is a compound of Formula (IA) or (I) whereinFormula (IA) or (I) wherein G is

and R₅ is H. In another embodiment is a compound of Formula (IA) or (I)wherein Formula (IA) or (I) wherein G is

R₅ is H, and p and q are 0. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₆-C₁₂aryl. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted phenyl. In another embodiment is a compound of Formula(IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₁-C₁₂heteroaryl. In another embodiment is a compoundof Formula (IA) or (I)wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted pyridine. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted pyrimidine. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted thiazole. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted thiophene. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted quinoline. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted imidazopyridine. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₁-C₆alkyl. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (IA) or (I)wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₂-C₇heterocycloalkyl. In another embodiment is acompound of Formula (IA) or(I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, and R₉ is

In another embodiment is a compound of Formula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₀, R₁₁, and R₁₂ are each H. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₁ and R₁₂ taken together form a bond.

In another embodiment is a compound of Formula (IA) or (I) wherein G is

In another embodiment is a compound of Formula (IA) or (I) wherein G is

and R₅ is H. In another embodiment is a compound of Formula (IA) or (I)wherein G is

R₅ is H, and p and q are 0. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₆-C₁₂aryl. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted phenyl. In another embodiment is a compound of Formula(IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₁-C₁₂heteroaryl. In another embodiment is a compoundof Formula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted pyridine. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted pyrimidine. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted thiazole. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted thiophene. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted quinoline. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted imidazopyridine. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₁-C₆alkyl. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₂-C₇heterocycloalkyl. In another embodiment is acompound of Formula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, and R₉ is

In another embodiment is a compound of Formula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₀, R₁₁, and R₁₂ are each H. In another embodiment is a compound ofFormula (IA) or (I) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R and R₁₂ taken together form a bond.

In another embodiment are compounds having the structure of Formula(Ia):

wherein:

G is

R₁ is —R₄, —CH₂R₄, —C(O)R₉, —C(O)C(O)R₉, —C(O)OR₄, —C(O)N(R₃)(R₄), or—S(O)₂R₉;each R₃ is independently is H, or substituted or unsubstitutedC₁-C₄alkyl;each R₄ is independently H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;R₅ is H, substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl; or R₁ and R₅ togetherwith the nitrogen atom to which they are attached are combined to form asubstituted or unsubstituted C₂-C₉heterocycloalkyl ring;each R₆ is independently halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂; or R₁ and R₆ arecombined to form a substituted or unsubstituted C₂-C₉heterocycloalkylring;each R₇ is independently halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂;R₉ is —R₄, or

R₁₀ is H, halogen, —CN, or -L₁-L₂;R₁₁ and R₁₂ are independently H, halogen, —CN, or -L₁-L₂; or R₁₁ and R₁₂taken together form a bond;each L₁ is optionally present and when present each L₁ is independentlysubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂aryl, substituted or unsubstituted C₁-C₁₂heteroaryl,—C(═O)—, —O—, or —S—;each L₂ is independently H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl,substituted or unsubstituted C₁-C₁₂heteroaryl or —N(R₁₃)₂;each R₁₃ is independently H, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₂-C₇ heterocycloalkyl, C₆-C₁₂aryl, orC₁-C₁₂heteroaryl;p is 0-3; andq is 0-3;or a pharmaceutically acceptable solvate, pharmaceutically acceptablesalt, or pharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (Ia) wherein G is

In another embodiment is a compound of Formula (Ia) wherein G is

and R₅ is H. In another embodiment is a compound of Formula (Ia) whereinG is

R₅ is H, and p and q are 0. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₆-C₁₂aryl. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted phenyl. In another embodiment is a compound of Formula(Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₁-C₁₂heteroaryl. In another embodiment is a compoundof Formula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted pyridine. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted pyrimidine. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted thiazole. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted thiophene. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted quinoline. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted imidazopyridine. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₁-C₆alkyl. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₂-C₇heterocycloalkyl. In another embodiment is acompound of Formula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, and R₉ is

In another embodiment is a compound of Formula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₀, R₁₁, and R₁₂ are each H. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₁ and R₁₂ taken together form a bond.

In another embodiment is a compound of Formula (Ia) wherein G is

In another embodiment is a compound of Formula (Ia) wherein G is

and R₅ is H. In another embodiment is a compound of Formula (Ia) whereinG is

R₅ is H, and p and q are 0. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₆-C₁₂aryl. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted phenyl. In another embodiment is a compound of Formula(Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₁-C₁₂heteroaryl. In another embodiment is a compoundof Formula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted pyridine. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted pyrimidine. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted thiazole. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted thiophene. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted quinoline. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted imidazopyridine. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₁-C₆alkyl. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is —R₄, and R₄ is substitutedor unsubstituted C₂-C₇-heterocycloalkyl. In another embodiment is acompound of Formula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, and R₉ is

In another embodiment is a compound of Formula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₀, R₁₁, and R₁₂ are each H. In another embodiment is a compound ofFormula (Ia) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₁ and R₁₂ taken together form a bond.

In another embodiment are compounds having the structure of Formula(II):

wherein:ring A is substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;Y is optionally present and when present is —CH₂O—, —OCH₂—, —OCH₂CH₂O—,—O—, —N(R₃)—, —C(O)—, —N(R₃)C(O)—, —C(O)N(R₃)—, —N(R₃)C(O)N(R₃)—,—S(O)—, —S(O)₂—, —N(R₃)S(O)₂—, —S(O)₂N(R₃)—, —C(═NH)—, —C(═NH)N(R₃)—, orsubstituted or unsubstituted C₁-C₄alkylene;Z is optionally present and when present is substituted or unsubstitutedC₁-C₃alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;

G is

R₁ is —C(O)R₉, —C(O)OR₄, —C(O)N(R₃)(R₄), or —S(O)₂R₉;each R₃ is independently is H, or substituted or unsubstitutedC₁-C₄alkyl;R₄ is substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl;R₅ is H, substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl;each R₆ and R₇ is independently halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂;R₉ is substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl,substituted or unsubstituted C₁-C₁₂heteroaryl, or

R₁₀ is H, halogen, —CN, or -L₁-L₂;R₁₁ and R₁₂ are independently H, halogen, —CN, or -L₁-L₂; or R₁₁ and R₁₂taken together form a bond;each L₁ is optionally present and when present each L₁ is independentlysubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂aryl, substituted or unsubstituted C₁-C₁₂heteroaryl,—C(═O)—, —O—, or —S—;each L₂ is independently H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl,substituted or unsubstituted C₁-C₁₂heteroaryl or —N(R₁₃)₂;each R₁₃ is independently H, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₂-C₇ heterocycloalkyl, C₆-C₁₂aryl, orC₁-C₁₂heteroaryl;p is 0-3; andq is 0-3;or a pharmaceutically acceptable solvate, pharmaceutically acceptablesalt, or pharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (II) wherein ring A issubstituted or unsubstituted C₃-C₆cycloalkyl. In another embodiment is acompound of Formula (II) wherein ring A is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(II) wherein ring A is substituted or unsubstituted C₆-C₁₂aryl. Inanother embodiment is a compound of Formula (II) wherein ring A issubstituted or unsubstituted C₁-C₁₂heteroaryl.

In another embodiment is a compound of Formula (II) wherein ring A issubstituted or unsubstituted phenyl. In another embodiment is a compoundof Formula (II) wherein ring A is substituted or unsubstituted phenyl, Yis absent, and Z is substituted or unsubstituted C₁-C₃alkyl, substitutedor unsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl. In another embodiment isa compound of Formula (II) wherein ring A is substituted orunsubstituted phenyl, Y is absent, and Z is substituted or unsubstitutedC₁-C₃alkyl. In another embodiment is a compound of Formula (II) whereinring A is substituted or unsubstituted phenyl, Y is absent, and Z issubstituted or unsubstituted C₃-C₆cycloalkyl. In another embodiment is acompound of Formula (II) wherein ring A is substituted or unsubstitutedphenyl, Y is absent, and Z is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(II) wherein ring A is substituted or unsubstituted phenyl, Y is absent,and Z is substituted or unsubstituted C₆-C₁₂aryl. In another embodimentis a compound of Formula (II) wherein ring A is substituted orunsubstituted phenyl, Y is absent, and Z is substituted or unsubstitutedC₁-C₁₂heteroaryl. In another embodiment is a compound of Formula (II)wherein ring A is substituted or unsubstituted phenyl, Y is absent, andZ is a substituted or unsubstituted pyrimidine. In another embodiment isa compound of Formula (II) wherein ring A is substituted orunsubstituted phenyl, Y is absent, and Z is a substituted orunsubstituted oxazole.

In another embodiment is a compound of Formula (II) wherein ring A issubstituted or unsubstituted phenyl, Y is —C(O)—, and Z is substitutedor unsubstituted C₁-C₃alkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₆-C₁₂aryl, or substituted or unsubstitutedC₁-C₁₂heteroaryl. In another embodiment is a compound of Formula (II)wherein ring A is substituted or unsubstituted phenyl, Y is —C(O)—, andZ is substituted or unsubstituted C₁-C₃alkyl. In another embodiment is acompound of Formula (II) wherein ring A is substituted or unsubstitutedphenyl, Y is —C(O)—, and Z is substituted or unsubstitutedC₃-C₆cycloalkyl. In another embodiment is a compound of Formula (II)wherein ring A is substituted or unsubstituted phenyl, Y is —C(O)—, andZ is substituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (II) wherein ring A is substitutedor unsubstituted phenyl, Y is —C(O)—, and Z is substituted orunsubstituted morpholine. In another embodiment is a compound of Formula(II) wherein ring A is substituted or unsubstituted phenyl, Y is —C(O)—,and Z is substituted or unsubstituted C₆-C₁₂aryl. In another embodimentis a compound of Formula (II) wherein ring A is substituted orunsubstituted phenyl, Y is —C(O)—, and Z is substituted or unsubstitutedC₁-C₁₂heteroaryl.

In another embodiment is a compound of Formula (II) wherein G is

In another embodiment is a compound of Formula (II) wherein G is

and R₅ is H. In another embodiment is a compound of Formula (II) whereinG is

R₅ is H, and p and q are 0. In another embodiment is a compound ofFormula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₆-C₁₂aryl. In another embodiment is a compound of Formula(II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₁-C₁₂heteroaryl. In another embodiment is a compound ofFormula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, and R₉ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, and R₉ is

In another embodiment is a compound of Formula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₀, R₁, and R₁₂ are each H. In another embodiment is a compound ofFormula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

R₁₀ and R₁₂ are each H, R₁₁ is -L₁-L₂, L₁ is —CH₂—, and L₂ is —N(CH₃)₂.In another embodiment is a compound of Formula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₁ and R₁₂ taken together form a bond.

In another embodiment is a compound of Formula (II) wherein G is

In another embodiment is a compound of Formula (II) wherein G is

and R₅ is H. In another embodiment is a compound of Formula (II) whereinG is

R₅ is H, and p and q are 0. In another embodiment is a compound ofFormula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₆-C₁₂aryl. In another embodiment is a compound of Formula(II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₁-C₁₂heteroaryl. In another embodiment is a compound ofFormula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, and R₉ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, and R₉ is

In another embodiment is a compound of Formula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₀, R₁₁, and R₁₂ are each H. In another embodiment is a compound ofFormula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

R₁₀ and R₁₂ are each H, R₁₁ is -L₁-L₂, L₁ is —CH₂—, and L₂ is —N(CH₃)₂.In another embodiment is a compound of Formula (II) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₁ and R₁₂ taken together form a bond.

In another embodiment are compounds having the structure of Formula(III):

wherein:ring A is substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇-heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;Y is optionally present and when present is —CH₂O—, —OCH₂—, —O—,—N(R₃)—, —C(O)—, —N(R₃)C(O)—, —C(O)N(R₃)—, —N(R₃)C(O)N(R₃)—, —S(O)—,—S(O)₂—, —N(R₃)S(O)₂—, —S(O)₂N(R₃)—, —C(═NH)—, —C(═NH)N(R₃)—, orsubstituted or unsubstituted C₁-C₄alkylene;Z is optionally present and when present is substituted or unsubstitutedC₁-C₃alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl;

G is

R₁ is —C(O)R₉, —C(O)OR₄, —C(O)N(R₃)(R₄), or —S(O)₂R₉;each R₃ is independently is H, or substituted or unsubstitutedC₁-C₄alkyl;R₄ is substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl;R₅ is H, substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl;each R₆ and R₇ is independently halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂;R₉ is substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, substituted or unsubstituted C₁-C₁₂heteroaryl, or

R₁₀ is H, halogen, —CN, or -L₁-L₂;R₁₁ and R₁₂ are independently H, halogen, —CN, or -L₁-L₂; or R₁₁ and R₁₂taken together form a bond;each L₁ is optionally present and when present each L₁ is independentlysubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂aryl, substituted or unsubstituted C₁-C₁₂heteroaryl,—C(═O)—, —O—, or —S—;each L₂ is independently H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl,substituted or unsubstituted C₁-C₁₂heteroaryl or —N(R₁₃)₂;each R₁₃ is independently H, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₂-C₇ heterocycloalkyl, C₆-C₁₂aryl, orC₁-C₁₂heteroaryl;p is 0-3; andq is 0-3;or a pharmaceutically acceptable solvate, pharmaceutically acceptablesalt, or pharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (III) wherein ring A issubstituted or unsubstituted C₃-C₆cycloalkyl. In another embodiment is acompound of Formula (III) wherein ring A is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(III) wherein ring A is substituted or unsubstituted C₆-C₁₂aryl. Inanother embodiment is a compound of Formula (III) wherein ring A issubstituted or unsubstituted C₁-C₁₂heteroaryl.

In another embodiment is a compound of Formula (III) wherein ring A issubstituted or unsubstituted phenyl. In another embodiment is a compoundof Formula (III) wherein ring A is substituted or unsubstituted phenyl,Y is absent, and Z is substituted or unsubstituted C₁-C₃alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂aryl, or substituted or unsubstituted C₁-C₁₂heteroaryl. In anotherembodiment is a compound of Formula (III) wherein ring A is substitutedor unsubstituted phenyl, Y is absent, and Z is substituted orunsubstituted C₁-C₃alkyl. In another embodiment is a compound of Formula(III) wherein ring A is substituted or unsubstituted phenyl, Y isabsent, and Z is substituted or unsubstituted C₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (III) wherein ring A issubstituted or unsubstituted phenyl, Y is absent, and Z is substitutedor unsubstituted C₂-C₇heterocycloalkyl. In another embodiment is acompound of Formula (III) wherein ring A is substituted or unsubstitutedphenyl, Y is absent, and Z is substituted or unsubstituted C₆-C₁₂aryl.In another embodiment is a compound of Formula (III) wherein ring A issubstituted or unsubstituted phenyl, Y is absent, and Z is substitutedor unsubstituted C₁-C₁₂heteroaryl. In another embodiment is a compoundof Formula (III) wherein ring A is substituted or unsubstituted phenyl,Y is absent, and Z is a substituted or unsubstituted pyrimidine. Inanother embodiment is a compound of Formula (III) wherein ring A issubstituted or unsubstituted phenyl, Y is absent, and Z is a substitutedor unsubstituted oxazole.

In another embodiment is a compound of Formula (III) wherein ring A issubstituted or unsubstituted phenyl, Y is —C(O)—, and Z is substitutedor unsubstituted C₁-C₃alkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₆-C₁₂aryl, or substituted or unsubstitutedC₁-C₁₂heteroaryl. In another embodiment is a compound of Formula (III)wherein ring A is substituted or unsubstituted phenyl, Y is —C(O)—, andZ is substituted or unsubstituted C₁-C₃alkyl. In another embodiment is acompound of Formula (III) wherein ring A is substituted or unsubstitutedphenyl, Y is —C(O)—, and Z is substituted or unsubstitutedC₃-C₆cycloalkyl. In another embodiment is a compound of Formula (III)wherein ring A is substituted or unsubstituted phenyl, Y is —C(O)—, andZ is substituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (III) wherein ring A is substitutedor unsubstituted phenyl, Y is —C(O)—, and Z is substituted orunsubstituted morpholine. In another embodiment is a compound of Formula(III) wherein ring A is substituted or unsubstituted phenyl, Y is—C(O)—, and Z is substituted or unsubstituted C₆-C₁₂aryl. In anotherembodiment is a compound of Formula (III) wherein ring A is substitutedor unsubstituted phenyl, Y is —C(O)—, and Z is substituted orunsubstituted C₁-C₁₂heteroaryl.

In another embodiment is a compound of Formula (III) wherein G is

In another embodiment is a compound of Formula (III) wherein G is

and R₅ is H. In another embodiment is a compound of Formula (III)wherein G is

R₅ is H, and p and q are 0. In another embodiment is a compound ofFormula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₆-C₁₂aryl. In another embodiment is a compound of Formula(III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₁-C₁₂heteroaryl. In another embodiment is a compound ofFormula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, and R₉ is

In another embodiment is a compound of Formula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₀, R₁₁, and R₁₂ are each H. In another embodiment is a compound ofFormula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

R₁₀ and R₁₂ are each H, R₁₁ is -L₁-L₂, L₁ is —CH₂—, and L₂ is —N(CH₃)₂.In another embodiment is a compound of Formula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₁ and R₁₂ taken together form a bond.

In another embodiment is a compound of Formula (III) wherein G is

In another embodiment is a compound of Formula (III) wherein G is

and R₅ is H. In another embodiment is a compound of Formula (III)wherein G is

R₅ is H, and p and q are 0. In another embodiment is a compound ofFormula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₆-C₁₂aryl. In another embodiment is a compound of Formula(III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₁-C₁₂heteroaryl. In another embodiment is a compound ofFormula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is substituted orunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (III) wherein G is

R₅ is H, p and q are 0, R 1 is —C(O)R₉, and R₉ is

In another embodiment is a compound of Formula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₀, R₁₁, and R₁₂ are each H. In another embodiment is a compound ofFormula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

R₁₀ and R₁₂ are each H, R₁₁ is -L₁-L₂, L₁ is —CH₂—, and L₂ is —N(CH₃)₂.In another embodiment is a compound of Formula (III) wherein G is

R₅ is H, p and q are 0, R₁ is —C(O)R₉, R₉ is

and R₁₁ and R₁₂ taken together form a bond.

In a particular embodiment, with respect to the compounds of Formula(IA), (I), (Ia), (II), (III), G is

In one embodiment, p is 0. In another embodiment, p is 1.

In another embodiment, with respect to the compounds of Formula (IA),(I), (Ia), (II), (III), G is

In one embodiment, R₅ is H or alkyl. In another embodiment, R₅ is H.

In another embodiment, with respect to the compounds of Formula (IA),(I), (Ia), (II), (III), G is

In a particular embodiment is a compound of Formula (IV) having thestructure

wherein A, W, X, Y, Z, R₁, R_(s), and R₆ are as described for Formula(I); provided that when W is N, and R₁ is H, t-Boc, or —C(O)—CH═CH₂;then X is other than C-Et or N.

In another embodiment is a compound of Formula (IV) wherein ring A issubstituted or unsubstituted C₃-C₆cycloalkyl. In another embodiment is acompound of Formula (IV) wherein ring A is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IV) wherein ring A is substituted or unsubstituted C₆-C₁₂aryl. Inanother embodiment is a compound of Formula (IV) wherein ring A issubstituted or unsubstituted C₁-C₁₂heteroaryl.

In another embodiment is a compound of Formula (IV) wherein ring A issubstituted or unsubstituted phenyl. In another embodiment is a compoundof Formula (IV) wherein ring A is substituted or unsubstituted phenyl, Yis absent, and Z is substituted or unsubstituted C₁-C₃alkyl, substitutedor unsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂aryl, orsubstituted or unsubstituted C₁-C₁₂heteroaryl. In another embodiment isa compound of Formula (IV) wherein ring A is substituted orunsubstituted phenyl, Y is absent, and Z is substituted or unsubstitutedC₁-C₃alkyl. In another embodiment is a compound of Formula (IV) whereinring A is substituted or unsubstituted phenyl, Y is absent, and Z issubstituted or unsubstituted C₃-C₆cycloalkyl. In another embodiment is acompound of Formula (IV) wherein ring A is substituted or unsubstitutedphenyl, Y is absent, and Z is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IV) wherein ring A is substituted or unsubstituted phenyl, Y is absent,and Z is substituted or unsubstituted C₆-C₁₂aryl. In another embodimentis a compound of Formula (IV) wherein ring A is substituted orunsubstituted phenyl, Y is absent, and Z is substituted or unsubstitutedC₁-C₁₂heteroaryl. In another embodiment is a compound of Formula (IV)wherein ring A is substituted or unsubstituted phenyl, Y is absent, andZ is a substituted or unsubstituted pyrimidine. In another embodiment isa compound of Formula (IV) wherein ring A is substituted orunsubstituted phenyl, Y is absent, and Z is a substituted orunsubstituted oxazole.

In another embodiment is a compound of Formula (IV) wherein ring A issubstituted or unsubstituted phenyl, Y is —C(O)—, and Z is substitutedor unsubstituted C₁-C₃alkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₆-C₁₂aryl, or substituted or unsubstitutedC₁-C₁₂heteroaryl. In another embodiment is a compound of Formula (IV)wherein ring A is substituted or unsubstituted phenyl, Y is —C(O)—, andZ is substituted or unsubstituted C₁-C₃alkyl. In another embodiment is acompound of Formula (IV) wherein ring A is substituted or unsubstitutedphenyl, Y is —C(O)—, and Z is substituted or unsubstitutedC₃-C₆cycloalkyl. In another embodiment is a compound of Formula (IV)wherein ring A is substituted or unsubstituted phenyl, Y is —C(O)—, andZ is substituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (IV) wherein ring A is substitutedor unsubstituted phenyl, Y is —C(O)—, and Z is substituted orunsubstituted morpholine. In another embodiment is a compound of Formula(IV) wherein ring A is substituted or unsubstituted phenyl, Y is —C(O)—,and Z is substituted or unsubstituted C₆-C₁₂aryl. In another embodimentis a compound of Formula (IV) wherein ring A is substituted orunsubstituted phenyl, Y is —C(O)—, and Z is substituted or unsubstitutedC₁-C₁₂heteroaryl.

In one embodiment, R₅ is H or alkyl. In another embodiment, R₅ is H.

In one embodiment, R₆ is halogen, —CN, —OH, —NH₂, substituted orunsubstituted C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, or —N(R₃)₂. In another embodiment,R₆ is substituted or unsubstituted C₁-C₄alkyl. In a particularembodiment, R₆ is Me.

In one embodiment, R₁ is —CH₂R₄, —C(O)R₉, —C(O)C(O)R₉, —C(O)OR₄,—C(O)N(R₃)(R₄), or —S(O)₂R₉. In a particular embodiment, R₁ is —C(O)R₉.

In one embodiment, R₉ is —R₄, and R₄ is substituted or unsubstitutedC₆-C₁₂aryl. In another embodiment, R₉ is —R₄, and R₄ is substituted orunsubstituted phenyl. In another embodiment, R₉ is —R₄, and R₄ issubstituted or unsubstituted heteroaryl. In another embodiment, R₉ is—R₄, and R₄ is substituted or unsubstituted pyridine or pyrimidine. Inanother embodiment, R₉ is —R₄, and R₄ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment, R₉ is —R₄, and R₄ is substituted orunsubstituted C₃-C₆cycloalkyl. In another embodiment, R₉ is —R₄, and R₄is substituted or unsubstituted C₂-C₇heterocycloalkyl.

In another embodiment, R₉ is

In another embodiment, R₉ is

and R₁₀, R₁, and R₁₂ are each H. In another embodiment, R₉ is

and R₁₁ and R₁₂ taken together form a bond.

In another embodiment, R₉ is

In one embodiment, X is C(R₂). In another embodiment, X is C(R₂); and R₂is substituted or unsubstituted C₁-C₄alkyl. In another embodiment, R₂ isMe, Et, i-Pr, or CF₃. In another embodiment, R₂ is CN. In anotherembodiment, R₂ is halogen. In another embodiment, R₂ is F, Cl, or Br. Ina particular embodiment, R₂ is H.

In one embodiment, R₅ is H, Me, Et, or i-Pr. In a particular embodiment,R₅ is H.

In another embodiment, X is N.

In one embodiment, W is C(R₂). In another embodiment, W is C(R₂); and R₂is substituted or unsubstituted C₁-C₄alkyl. In another embodiment, R₂ isMe, Et, i-Pr, or CF₃. In another embodiment, R₂ is CN. In anotherembodiment, R₂ is halogen. In another embodiment, R₂ is F, Cl, or Br. Ina particular embodiment, R₂ is H.

In another embodiment, W is N.

In another particular embodiment is a compound of Formula (Va), (Vb),(Vc), (Vd), (Ve), (Vf), (Vg), or (Vh) having the structure:

wherein A, W, X, Y, Z, R₁, R₃, R₄, and R₆ are as described for Formula(I);R_(9a) is substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₃-C₆heterocycloalkyl, substituted or unsubstituted C₁-C₄alkoxy,substituted or unsubstituted phenoxy, halo, or CN; and t is 1, 2, or 3.

In one embodiment, the compound is according to Formula (Va). In anotherembodiment, the compound is according to Formula (Vb). In anotherembodiment, the compound is according to Formula (Vc). In anotherembodiment, the compound is according to Formula (Vd). In anotherembodiment, the compound is according to Formula (Ve). In anotherembodiment, the compound is according to Formula (Vf). In anotherembodiment, the compound is according to Formula (Vg). In anotherembodiment, the compound is according to Formula (Vh).

In one embodiment, R_(9a) is Me, Et, i-Pr, t-Bu, cyclopropyl, OMe, F, orCl.

In one embodiment, each of R₃ and R₄ is independently H, or Me. Inanother embodiment, R₄ is substituted or unsubstituted phenyl. In aparticular embodiment, R₄ is Me, Et, or 2-chlorophenyl.

In one embodiment, R₁ is Me, Et, —C(O)NMe₂, or —C(O)-cyclopropyl.

In one embodiment, R₆ is H, Me, Et, or hydroxymethyl. In anotherembodiment, R₆ is Me or CH₂OH. In a particular embodiment, R₆ is (R)-Me.

In one embodiment, t is 1. In another embodiment, t is 2. In anotherembodiment, t is 3.

In one embodiment, each of W and X is N. In another embodiment, W is N;and X is CH.

In one embodiment, ring A is substituted or unsubstituted phenyl,substituted or unsubstituted pyridyl, substituted or unsubstitutedquinolinyl, substituted or unsubstituted thiazolyl, substituted orunsubstituted isothiazolyl, substituted or unsubstituted oxazolyl,substituted or unsubstituted isoxazolyl, substituted or unsubstitutedbenzothiazolyl. In another embodiment, ring A is substituted orunsubstituted phenyl, or substituted or unsubstituted isothiazolyl.

In one embodiment, Y is absent. In another embodiment, Y is —O—, or—S(O)₂—.

In one embodiment, Z is as described for Formula (I). In anotherembodiment, Z is substituted or unsubstituted alkyl, or substituted orunsubstituted phenyl.

In another embodiment, Y is absent; and Z is halo, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocycloalkyl.

In another embodiment, Y is absent; and Z is Cl, F, Me, Et, i-Pr,substituted or unsubstituted cyclopropyl, substituted or unsubstitutedpyranyl, substituted or unsubstituted piperidinyl, substituted orunsubstituted piperizinyl, or substituted or unsubstituted morpholinyl.

In another embodiment, Y is absent; and Z is cyclopropyl unsubstitutedor substituted with CN, or amido.

In another embodiment, Y is absent; and Z is piperidinyl unsubstitutedor substituted with alkyl, cycloalkyl, phenyl, or pyridyl each of whichis unsubstituted or substituted with one, two or three substituted orunsubstituted alkyl, or unsubstituted or substituted acyl.

In another embodiment, Y is absent; and Z is piperizinyl unsubstitutedor substituted with alkyl, cycloalkyl, phenyl, or pyridyl each of whichis unsubstituted or substituted with one, two or three substituted orunsubstituted alkyl, or unsubstituted or substituted acyl.

In a particular embodiment, the group -A-Y—Z is:

wherein Z is as described for Formula (I); R₁₄ is substituted orunsubstituted C₁-C₄alkyl, substituted or unsubstituted C₁-C₄acyl,substituted or unsubstituted C₃-C₆cycloalkyl, or —C(O)NR_(14a)R_(14b);each of R_(14a) and R_(14b) is independently substituted orunsubstituted C₁-C₄alkyl or R_(14a) and R_(14b) together with the N theyare attached to form a substituted or unsubstitutedC₂-C₉heterocycloalkyl ring; each of R₁₅ and R₁₆ is independently H,substituted or unsubstituted C₁-C₄alkyl, CN, or —C(O)NR_(14a)R_(14b).

In one embodiment, R₁₄ is Me, Et, i-Pr, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. In a particular embodiment, R₁₄ iscyclopropyl, cyclobutyl, or cyclopentyl. In another particularembodiment, R₁₄ is C(O)Me, or C(O)Et. In one embodiment, R₁₅ is H, Me,or CN. In one embodiment, R₁₆ is H, Me, CF₃, CN, CH₂—NH₂, OH, NH₂,—C(O)NH₂, or —C(O)NMe₂. In one embodiment, Z is Me, Et, i-Pr,cyclopropyl, or Ph.

In a more particular embodiment, R₁₄ is —C(O)Et, cyclopropyl,cyclobutyl, or cyclopentyl; and R₁₅ is H, CN, or Me.

In a more particular embodiment, the group -A-Y—Z is:

In another particular embodiment is a compound of Formula (VIa), or(VIb) having the structure:

wherein A, W, X, Y, Z, and R₅ are as described for Formula (I);R_(10a) is H, substituted or unsubstituted C₁-C₄alkyl; and t is 1, 2, or3;provided that when W is N; then X is CH or N.

In one embodiment, the compound is according to Formula (VIa). Inanother embodiment, the compound is according to Formula (VIb).

In one embodiment, R_(10a) is H, Me, CH₂—NMe₂, or CH₂—N(Me)-cyclopropyl.In a particular embodiment, the compound is according to Formula (VIb),and R_(10a) is Me. In one embodiment, t is 1. In another embodiment, tis 2. In another embodiment, t is 3.

In one embodiment, each of W and X is N. In another embodiment, W is N;and X is CH.

In one embodiment, ring A is substituted or unsubstituted phenyl,substituted or unsubstituted pyridyl, substituted or unsubstitutedquinolinyl, substituted or unsubstituted thiazolyl, substituted orunsubstituted isothiazolyl, substituted or unsubstituted oxazolyl,substituted or unsubstituted isoxazolyl, substituted or unsubstitutedbenzothiazolyl. In another embodiment, ring A is substituted orunsubstituted phenyl, or substituted or unsubstituted isothiazolyl.

In one embodiment, Y is absent. In another embodiment, Y is —O—, or—S(O)₂—.

In one embodiment, Z is as described for Formula (I). In anotherembodiment, Z is substituted or unsubstituted alkyl, or substituted orunsubstituted phenyl.

In another embodiment, Y is absent; and Z is halo, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocycloalkyl.

In another embodiment, Y is absent; and Z is Cl, F, Me, Et, i-Pr,substituted or unsubstituted cyclopropyl, substituted or unsubstitutedpyranyl, substituted or unsubstituted piperidinyl, substituted orunsubstituted piperizinyl, or substituted or unsubstituted morpholinyl.

In another embodiment, Y is absent; and Z is cyclopropyl unsubstitutedor substituted with CN, or amido.

In another embodiment, Y is absent; and Z is piperidinyl unsubstitutedor substituted with alkyl, cycloalkyl, phenyl, or pyridyl each of whichis unsubstituted or substituted with one, two or three substituted orunsubstituted alkyl, or unsubstituted or substituted acyl.

In another embodiment, Y is absent; and Z is piperizinyl unsubstitutedor substituted with alkyl, cycloalkyl, phenyl, or pyridyl each of whichis unsubstituted or substituted with one, two or three substituted orunsubstituted alkyl, or unsubstituted or substituted acyl.

In another embodiment is a compound of Formula (IA), (I), (Ia), (II),(III), (IV), (Va)-(Vh), or (VIa)-(VIb) wherein ring A is substituted orunsubstituted C₁-C₁₂heteroaryl. In a particular embodiment, ring A ispyridyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl.

In a particular embodiment, the group -A-Y—Z is:

wherein Z is as described for Formula (I); R₁₄ is substituted orunsubstituted C₁-C₄alkyl, substituted or unsubstituted C₁-C₄acyl,substituted or unsubstituted C₃-C₆cycloalkyl, or —C(O)NR_(14a)R_(14b);each of R_(14a) and R_(14b) is independently substituted orunsubstituted C₁-C₄alkyl or R_(14a) and R_(14b) together with the N theyare attached to form a substituted or unsubstitutedC₂-C₉heterocycloalkyl ring; each of R₁₅ and R₁₆ is independently H,substituted or unsubstituted C₁-C₄alkyl, CN, or —C(O)NR_(14a)R_(14b).

In one embodiment, R₁₄ is Me, Et, i-Pr, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. In a particular embodiment, R₁₄ iscyclopropyl, cyclobutyl, or cyclopentyl. In another particularembodiment, R₁₄ is C(O)Me, or C(O)Et. In one embodiment, R₁₅ is H, Me,or CN. In one embodiment, R₁₆ is H, Me, CF₃, CN, CH₂—NH₂, OH, NH₂,—C(O)NH₂, or —C(O)NMe₂. In one embodiment, Z is Me, Et, i-Pr,cyclopropyl, or Ph.

In a more particular embodiment, R₁₄ is —C(O)Et, cyclopropyl,cyclobutyl, or cyclopentyl; and R₁₅ is H, CN, or Me.

In a more particular embodiment, the group -A-Y—Z is:

In a particular embodiment, the compound is any one of compoundsselected from the group consisting of:

-   3-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-tert-butylbenzamido)pyrrolidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(trifluoroacetamido)pyrrolidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-3-{[4-(morpholine-4-carbonyl)phenyl]amino}pyrazine-2-carboxamide;-   3-[(3R)-3-cyclopropaneamidopiperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-{[(3R)-1-(4-tert-butylbenzoyl)piperidin-3-yl]amino}-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-{[(3R)-1-cyclopropanecarbonylpiperidin-3-yl]amino}-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-{[(3R)-1-(prop-2-enoyl)piperidin-3-yl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-methylbenzamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-[4-(trifluoromethyl)benzamido]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-cyanobenzamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-chlorobenzamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-fluorobenzamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-cyclobutaneamidopiperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-[(pyrrolidine-1-carbonyl)amino]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-propanamidopiperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(prop-2-enamido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-cyclopropylbenzamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(cyclopentylamino)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-[(propan-2-yl)amino]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-ethanesulfonamidopiperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-aminopiperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-[(morpholine-4-carbonyl)amino]piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   tert-butyl    (3R)-3-[(6-carbamoyl-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazin-3-yl)amino]pyrrolidine-1-carboxylate;-   tert-butyl    (3R)-3-[(6-carbamoyl-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazin-3-yl)amino]piperidine-1-carboxylate;-   3-[(3R)-3-(2-cyanoacetamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(1-cyanocyclopropaneamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(2-methylpropanamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(pyridine-3-amido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-benzamidopiperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-{[(3R)-pyrrolidin-3-yl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-{[(3R)-piperidin-3-yl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-{[(3R)-1-(prop-2-enoyl)pyrrolidin-3-yl]amino}-1,2,4-triazine-6-carboxamide;-   3-{[(3R)-1-[(2E)-4-[cyclopropyl(methyl)amino]but-2-enoyl]pyrrolidin-3-yl]amino}-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-{[(3R)-1-propanoylpiperidin-3-yl]amino}-1,2,4-triazine-6-carboxamide;-   3-{[(3R)-1-[(2E)-4-[cyclopropyl(methyl)amino]but-2-enoyl]piperidin-3-yl]amino}-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-{[(3R)-1-[(2E)-4-(dimethylamino)but-2-enoyl]piperidin-3-yl]amino}-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-benzenesulfonamidopiperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(pyridine-4-amido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(pyridine-2-amido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-benzamidopyrrolidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(oxane-4-amido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(1-methylpiperidine-4-amido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(1-acetylpiperidine-4-amido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-cyclopentaneamidopiperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(5-chlorothiophene-2-amido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   N-[(3R)-1-(6-carbamoyl-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazin-3-yl)piperidin-3-yl]quinoline-3-carboxamide;-   3-[(3R)-3-(N-methyl4-tert-butylbenzamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-5-[(5-fluoropyridin-3-yl)amino]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-5-[(4-methylphenyl)amino]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-5-[(3-methylphenyl)amino]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-5-{[4-(pyrimidin-2-yl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-5-{[3-(pyrimidin-2-yl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(2-oxopyrrolidin-1-yl)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-{methyl[(3R)-1-(prop-2-enoyl)pyrrolidin-3-yl]amino}-5-{[4-(morpholine-4-carbonyl)phenyl]amino    1}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(isoquinolin-1-yloxy)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(pyrimidine-2-amido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(1,3-thiazole-2-amido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(1-cyclopropylpiperidine-4-amido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(1-cyclopentylpiperidine-4-amido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(but-2-ynamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-{imidazo[1,2-a]pyridine-6-amido}piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-{imidazo[1,2-a]pyridine-7-amido}piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-5-{[4-(1,3-oxazol-2-yl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-[(morpholine-4-carbonyl)amino]piperidin-1-yl]-5-{[4-(1,3-oxazol-2-yl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-{[methyl(phenyl)carbamoyl]amino}piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-{[4-(piperidin--yl)piperidine-1-carbonyl]amino}piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-5-[(4-methanesulfonylphenyl)amino]-1,2,4-triazine-6-carboxamide;-   5-{methyl[(3R)-1-(prop-2-enoyl)piperidin-3-yl]amino}-3-{[4-(morpholine-4-carbonyl)phenyl]amino}pyrazine-2-carboxamide;-   5-{[(3R)-1-[(2E)-4-(dimethylamino)but-2-enoyl]piperidin-3-yl](methyl)amino}-3-{[4-(morpholine-4-carbonyl)phenyl]amino}pyrazine-2-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-{[(propan-2-yloxy)carbonyl]({[(propan-2-yloxy)carbonyl]amino})amino}piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(6-cyclopropyl-8-fluoro-1-oxo-1,2-dihydroisoquinolin-2-yl)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-[(6-cyclopropyl-8-fluoroisoquinolin-1-yl)oxy]piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-[(phenylcarbamoyl)amino]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   N-[(3R)-1-(6-carbamoyl-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazin-3-yl)piperidin-3-yl]quinoline-2-carboxamide;-   N-[(3R)-1-(6-carbamoyl-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazin-3-yl)piperidin-3-yl]quinoline-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(1-oxo-2,3-dihydro-H-isoinindol-2-yl)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-[4-(2,2,2-trifluoroethoxy)benzamido]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(5-methylthiophene-2-amido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(4-tert-butylbenzamido)piperidin-1-yl]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-{[(3R)-1-(but-2-ynoyl)piperidin-3-yl](methyl)amino}-3-{[4-(morpholine-4-carbonyl)phenyl]amino}pyrazine-2-carboxamide;-   5-{[(3R)-1-[(2E)-4-[cyclopropyl(methyl)amino]but-2-enoyl]piperidin-3-yl](methyl)amino}-3-{[4-(morpholine-4-carbonyl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[(3R)-1-(but-2-ynoyl)piperidin-3-yl]amino}-5-[(4-methanesulfonylphenyl)amino]-1,2,4-triazine-6-carboxamide;-   3-{[(3R)-1-[(2E)-4-(dimethylamino)but-2-enoyl]piperidin-3-yl]amino}-5-[(4-methanesulfonylphenyl)amino]-1,2,4-triazine-6-carboxamide;-   3-{[(3R)-1-[(2E)-4-[cyclopropyl(methyl)amino]but-2-enoyl]piperidin-3-yl]amino}-5-[(4-methanesulfonylphenyl)amino]-1,2,4-triazine-6-carboxamide;-   3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-[(3R)-3-{[(4-tert-butylphenyl)carbamoyl]amino}piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-{[(4-methoxyphenyl)carbamoyl]amino}piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-ethoxybenzamido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(4-propoxybenzamido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-[4-(propan-2-yloxy)benzamido]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(5-methyl-1,2-oxazole-3-amido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   N-[(3R)-1-(6-carbamoyl-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazin-3-yl)piperidin-3-yl]-1-(propan-2-yl)-1H-1,2,3-benzotriazole-5-carboxamide;-   3-[(3R)-3-(5-methyl-1,3-thiazole-2-amido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(2-methyl-1,3-thiazole-5-amido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   N-[(3R)-1-(6-carbamoyl-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazin-3-yl)piperidin-3-yl]-1,3-benzothiazole-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(1-propanoylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-({4-[1-(cyanomethyl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-({4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;-   3-[(3R)-3-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-(4-phenoxybenzamido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-{[3-fluoro-4-(morpholin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   N-[(3R)-1-(6-carbamoyl-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazin-3-yl)piperidin-3-yl]-1,3-benzoxazole-2-carboxamide;-   5-{[(3R)-1-[(2E)-4-(dimethylamino)but-2-enoyl]piperidin-3-yl](methyl)amino}-3-[(4-phenoxyphenyl)amino]pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-[(3-methyl-1,2-thiazol-5-yl)amino]pyrazine-2-carboxamide;-   3-[(3R)-3-(4-methyl-1,3-thiazole-2-amido)piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-({4-[2-(dimethylamino)ethoxy]phenyl}amino)-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-({4-[2-(dimethyl-oxo-$l̂{5}-azanyl)ethoxy]phenyl}amino)-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(dimethylcarbamoyl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-({4-[4-(dimethylcarbamoyl)piperidin-1-yl]phenyl}amino)-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   N-[(3R)-1-(6-carbamoyl-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazin-3-yl)piperidin-3-yl]-1-ethyl-1H-1,2,3-benzotriazole-5-carboxamide;-   N-[(3R)-1-(6-carbamoyl-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazin-3-yl)piperidin-3-yl]-1-cyclopropyl-1H-1,2,3-benzotriazole-5-carboxamide;-   N-[(3R)-1-(6-carbamoyl-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazin-3-yl)piperidin-3-yl]-1-propyl-1H-1,2,3-benzotriazole-5-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-{[4-(propan-2-yl)piperidine-1-carbonyl]amino}piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-({4-[1-(propan-2-yl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-formylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-{[4-(morpholine-4-carbonyl)phenyl]amino}-3-[(3R)-3-[2-oxo-2-(piperidin-1-yl)acetamido]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(morpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-[(6-ethoxypyridin-3-yl)amino]-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-[(4-methanesulfonylphenyl)amino]-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(2-oxo-1,2-dihydropyridin-1-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-methanesulfonylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-({4-[1-(2-cyanoacetyl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-[(4-methanesulfonylphenyl)amino]-5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(2-ethoxyethoxy)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-[(4-ethoxyphenyl)amino]-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(oxan-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(2-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-5-[(quinolin-3-yl)amino]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-5-[(quinolin-7-yl)amino]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-({4-[1-(dimethylcarbamoyl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-3-{[4-(1-propanoylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-acetylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-formylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[6-(morpholin-4-yl)pyridin-3-yl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-[(quinolin-6-yl)amino]pyrazine-2-carboxamide;-   3-[(1,3-benzothiazol-6-yl)amino]-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-[(4-methoxyphenyl)amino]pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(2-methoxyethoxy)phenyl]amino}pyrazine-2-carboxamide;-   3-({4-[1-(2-cyanoacetyl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(4-methanesulfonylphenyl)amino]pyrazine-2-carboxamide;-   3-[(3R)-3-[(diethylcarbamoyl)amino]piperidin-1-yl]-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-({4-[1-(2-cyanoacetyl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(piperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-propanoylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(4-cyanophenyl)amino]-3-[(3R)-3-(4-ethoxybenzamido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-{[4-(1-ethylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-5-{[4-(1-propanoylpiperidin-4-yl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(1-acetylpiperidin-4-yl)phenyl]amino}-3-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-{[4-(1-formylpiperidin-4-yl)phenyl]amino}-3-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-ethoxybenzamido)piperidin-1-yl]-5-{[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(N,N-dimethylcarbamimidoyl)phenyl]amino}-3-[(3R)-3-(4-ethoxybenzamido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-ethoxybenzamido)piperidin-1-yl]-5-{[4-(pyrrolidine-1-carboximidoyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-3-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-({4-[1-(2-cyanoacetyl)piperidin-4-yl]phenyl})amino)-3-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-5-({4-[1-(prop-2-enoyl)piperidin-4-yl]phenyl}amino)-1,2,4-triazine-6-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-{[ethyl(methyl)carbamoyl]amino}piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-[(diethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(4-fluorobenzamido)piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(4-ethoxybenzamido)piperidin-1-yl]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(propan-2-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-{[4-(piperidin-4-yl)phenyl]amino}-3-[(3R)-3-[(piperidine-1-carbonyl)amino]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-5-{[4-(piperidin-4-yl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   5-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-3-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-{[4-(4-cyclopentylpiperazin-1-yl)phenyl]amino}-3-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-({4-[4-(dimethylcarbamoyl)piperidin-1-yl]phenyl}amino)-3-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)(methyl)amino]piperidin-1-yl]-3-{[4-(1,1-dioxo-1⁶-thiomorpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[2-fluoro-4-(piperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[3-fluoro-4-(piperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)(methyl)amino]piperidin-1-yl]-3-{[4-(1-propanoylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)(methyl)amino]piperidin-1-yl]-3-({4-[1-(dimethylcarbamoyl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)(methyl)amino]piperidin-1-yl]-3-{[4-(1-methanesulfonylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)(methyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-{imidazo[1,2-a]pyridine-6-amido}piperidin-1-yl]-3-{[4-(oxan-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-{5-hydroxyimidazo[1,2-a]pyridine-6-amido}piperidin-1-yl]-3-{[4-(oxan-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(4-methoxybenzamido)piperidin-1-yl]-3-{[4-(piperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1,1-dioxo-1⁶-thiomorpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-ethylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-{[ethyl(methyl)carbamoyl]amino}piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-propanamidopiperidin-1-yl]pyrazine-2-carboxamide;-   5-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-3-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   5-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-3-[(3R)-3-propanamidopiperidin-1-yl]-1,2,4-triazine-6-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-fluorobenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-(phenylamino)pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(4-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-ethylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-[(4-chlorophenyl)amino]-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(propan-2-yl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;-   4-[4-({(3-carbamoyl-6-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-1-(propan-2-yl)piperidin-1-ium-1-olate;-   3-[(4-chloro-3-methoxyphenyl)amino]-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(3-methoxy-4-methylphenyl)amino]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(4-methyl-1-propanoylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-({4-[1-(dimethylcarbamoyl)-4-methylpiperidin-4-yl]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(4-cyclopropylpiperazin-1-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(4-fluorophenyl)amino]pyrazine-2-carboxamide;-   3-{[4-(4-cyclopentylpiperazin-1-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[(pyridin-2-yl)carbamoyl]phenyl}amino)pyrazine-2-carboxamide;-   5-[(3R)-3-{[methyl(phenyl)carbamoyl]amino}piperidin-1-yl]-3-(phenylamino)pyrazine-2-carboxamide;-   3-{[2-chloro-4-(piperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(dimethylcarbamoyl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;-   3-{[4-(1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(oxan-4-yl)piperidin-4-yl]phenyl)}amino)pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(4-{1-[2-(2-hydroxyethoxy)ethyl]piperidin-4-yl}phenyl)amino]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropanecarbonylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-methanesulfonylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   ethyl    N-[(3R)-1-(5-carbamoyl-6-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazin-2-yl)piperidin-3-yl]carbamate;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(5-fluoro-6-methylpyridin-2-yl)amino]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(pyridin-2-yl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(dimethylcarbamoyl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(pyrrolidine-1-carbonyl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(1-phenylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclohexylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-aminopiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-formamidopiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-methanesulfonamidopiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-ethanesulfonamidopiperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-benzamidopiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(pyridine-3-amido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(5-fluoropyridine-3-amido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(2-oxopyrrolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-cyclopropaneamidopiperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-ethyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(2    S,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-({4-[4-methyl-1-(propan-2-yl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-({4-[4-methyl-1-(oxetan-3-yl)piperidin-4-yl]phenyl}amino)-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-formyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(4-methyl-1-propanoylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropanecarbonyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylsulfamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(dimethylsulfamoyl)piperidin-4-yl]phenyl}amino)pyrazine-2-carboxamide;-   5-[(2R,3R)-3-amino-2-methylpiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(2S,3R)-3-amino-2-methylpiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-aminopiperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-[(4-cyclohexylphenyl)amino]-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyanocyclopentyl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-{spiro[3.3]heptane-2-amido}piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4-phenylbenzamido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(6-phenylpyridine-3-amido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(2R,3R)-3-benzamido-2-methylpiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(2S,3R)-3-benzamido-2-methylpiperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(1-benzothiophene-2-amido)piperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(3-chlorobenzamido)piperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(4-chlorobenzamido)piperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-(5-chlorothiophene-2-amido)piperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-cyclopentaneamidopiperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(4,5,6,7-tetrahydro-1-benzothiophene-2-amido)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-(5-chloropyridine-3-amido)piperidin-1-yl]-3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(naphthalene-2-amido)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyano-1-methylethyl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-carbamoyl-1-methylethyl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyanocyclopentyl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-carbamoylcyclopentyl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3aR,7aR)-1-(dimethylcarbamoyl)-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3aR,7aR)-1-cyclopropanecarbonyl-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyanocyclopropyl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-carbamoylcyclopropyl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(4-cyano-1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3aR,7aR)-octahydro-1H-pyrrolo[3,2-b]pyridin-4-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[3-(3-chlorophenyl)-2-oxoimidazolidin-1-yl]piperidin-1-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(4-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-(phenylamino)pyrazine-2-carboxamide;-   5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)pyrazine-2-carboxamide;-   5-[(3aR,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridin-6-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxo-1,3-diazinan-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R,4R)-3-[(dimethylcarbamoyl)amino]-4-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3    aS,7aR)-1-(dimethylcarbamoyl)-octahydro-1H-pyrrolo[2,3-c]pyridin-6-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3    aS,7aR)-1-cyclopropanecarbonyl-octahydro-1H-pyrrolo[2,3-c]pyridin-6-yl]-3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(4-methyl-1-propanoylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino})-5-[(3R)-3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]-3-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)pyrazine-2-carboxamide;-   3-{[4-(1-cyanocyclopropyl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-carbamoylcyclopropyl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-({4-[1-(aminomethyl)cyclopentyl]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-({4-[1-(dimethylcarbamoyl)cyclopropyl]phenyl}amino)pyrazine-2-carboxamide;-   5-[(3R)-3-({[3-chloro-5-(trifluoromethyl)phenyl](methyl)carbamoyl}amino)piperidin-1-yl]-3-[(4-fluorophenyl)amino]pyrazine-2-carboxamide;-   5-[(3R)-3-({[3-chloro-5-(trifluoromethyl)phenyl](methyl)carbamoyl}amino)piperidin-1-yl]-3-{[4-(1-cyanocyclopropyl)phenyl]amino}pyrazine-2-carboxamide;-   3-{[4-(1-carbamoylcyclopropyl)phenyl]amino}-5-[(3R)-3-({[3-chloro-5-(trifluoromethyl)phenyl](methyl)carbamoyl}amino)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxo-1,3-diazinan-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxo-1,3-diazinan-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-[(1-cyclopropyl-1H-pyrazol-4-yl)amino]-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-[(1-cyclopentyl-1H-pyrazol-4-yl)amino]-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxo-1,3-diazinan-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-ethyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-2-methyl-3-(3-methyl-2-oxo-1,3-diazinan-1-yl)piperidin-1-yl]pyrazine-2-carboxamide;-   3-({4-[1-(aminomethyl)cyclopropyl]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-({4-[(dimethylamino)methyl]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]azepan-1-yl]pyrazine-2-carboxamide;-   3-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-cyclopropaneamidoazepan-1-yl]pyrazine-2-carboxamide;-   3-{[1-(1-cyclopentylazetidin-3-yl)-1H-pyrazol-4-yl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[1-(1-cyclopentylpiperidin-4-yl)-1H-pyrazol-4-yl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   3-{[1-(1-cyclopropanecarbonylpiperidin-4-yl)-1H-pyrazol-4-yl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   (4aR,8aR)-5-(5-carbamoyl-6-{[4-(1-cyclopentylpiperidin-4-yl)phenyl]amino}pyrazin-2-yl)-N,N-dimethyl-decahydro-1,5-naphthyridine-1-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(3-methyl-1,2-thiazol-5-yl)amino]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(propan-2-yloxy)phenyl]amino}pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-{[4-(2-methoxyethoxy)phenyl]amino}pyrazine-2-carboxamide;-   3-({4-[2-(dimethylamino)ethoxy]phenyl}amino)-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]-3-[(4-nitrophenyl)amino]pyrazine-2-carboxamide;-   3-{[4-(1-cyclobutylpiperidin-4-yl)phenyl]amino}-5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-ethylpiperidin-1-yl]pyrazine-2-carboxamide;-   3-{[(3R)-1-(but-2-ynoyl)pyrrolidin-3-yl]amino}-5-{[4-(morpholine-4-carbonyl)phenyl]amino}-1,2,4-triazine-6-carboxamide;-   3-{[4-(cyclopentyloxy)phenyl]amino}-5-[(3R)-3-[(dimethylcarbamoyl)amino]piperidin-1-yl]pyrazine-2-carboxamide;-   5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]-3-[(3-methyl    -1,2-thiazol-5-yl)amino]pyrazine-2-carboxamide;-   5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]-3-{[4-(propan-2-yloxy)phenyl]amino}pyrazine-2-carboxamide;    and-   5-[(2R,3R)-3-[(dimethylcarbamoyl)amino]-2-methylpiperidin-1-yl]-3-[(4-methanesulfonylphenyl)amino]pyrazine-2-carboxamide;

or a pharmaceutically acceptable solvate, pharmaceutically acceptablesalt, or pharmaceutically acceptable prodrug thereof.

At least some of the chemical names of compounds of the invention asgiven and set forth in this application, may have been generated on anautomated basis by use of a commercially available chemical namingsoftware program, and have not been independently verified.Representative programs performing this function include the Chemdrawnaming tool sold by Cambridge Software, Inc. and the Instant JChemSoftware tool sold by ChemAxon, Inc. In the instance where the indicatedchemical name and the depicted structure differ, the depicted structurewill control.

In another aspect is a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (IA), (I),(Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof, and a pharmaceuticallyacceptable excipient. In one embodiment, the pharmaceutical compositioncomprising the compound of Formula (IA), (I), (Ia), (II), (III), (IV),(Va)-(Vh), or (VIa)-(VIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or pharmaceutically acceptableprodrug thereof, is formulated for a route of administration selectedfrom oral administration, parenteral administration, buccaladministration, nasal administration, topical administration, or rectaladministration.

In another aspect is a method for treating an autoimmune disease orcondition comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (IA), (I),(Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof. In one embodiment theautoimmune disease is selected from rheumatoid arthritis or lupus. In afurther aspect is a method for treating a heteroimmune disease orcondition comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (IA), (I),(Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof. In yet anotherembodiment is a method for treating a cancer comprising administering toa patient in need a therapeutically effective amount of a compound ofFormula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof. In oneembodiment the cancer is a B-cell proliferative disorder. In anotherembodiment the B-cell proliferative disorder is diffuse large B celllymphoma, follicular lymphoma, mantel cell lymphoma, or chroniclymphocytic leukemia.

In yet a further aspect is a method for treating mastocytosis comprisingadministering to a patient in need a therapeutically effective amount ofa compound of Formula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or(VIa)-(VIb), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or pharmaceutically acceptable prodrug thereof.

In another aspect is a method for treating osteoporosis or boneresorption disorders comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (IA), (I),(Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof.

In a further aspect is a method for treating an inflammatory disease orcondition comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (IA), (I),(Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof.

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

In some embodiments, the compounds of Formula (IA), (I), (Ia), (II),(III), (IV), (Va)-(Vh), or (VIa)-(VIb) reversibly inhibit Btk and inother embodiments are used to treat patients suffering from Bruton'styrosine kinase-dependent or Bruton's tyrosine kinase mediatedconditions or diseases, including, but not limited to, cancer,autoimmune and other inflammatory diseases.

In some embodiments, the compounds of Formula (IA), (I), (Ia), (II),(III), (IV), (Va)-(Vh), or (VIa)-(VIb) irreversibly inhibit Btk and inother embodiments are used to treat patients suffering from Bruton'styrosine kinase-dependent or Bruton's tyrosine kinase mediatedconditions or diseases, including, but not limited to, cancer,autoimmune and other inflammatory diseases.

Preparation of Compounds

Compounds of any of Formula (IA), (I), (Ia), (II), (III), (IV),(Va)-(Vh), or (VIa)-(VIb) may be synthesized using standard syntheticreactions known to those of skill in the art or using methods known inthe art. The reactions can be employed in a linear sequence to providethe compounds or they may be used to synthesize fragments which aresubsequently joined by the methods known in the art.

Described herein are compounds that inhibit the activity of tyrosinekinase(s), such as Btk, and processes for their preparation. Alsodescribed herein are pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, pharmaceutically active metabolites andpharmaceutically acceptable prodrugs of such compounds. Pharmaceuticalcompositions that include at least one such compound or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,pharmaceutically active metabolite or pharmaceutically acceptableprodrug of such compound, are provided.

The starting material used for the synthesis of the compounds describedherein may be synthesized or can be obtained from commercial sources,such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.),Bachem (Torrance, Calif.), or Sigma Chemical Co. (St. Louis, Mo.). Thecompounds described herein, and other related compounds having differentsubstituents can be synthesized using techniques and materials known tothose of skill in the art, such as described, for example, in March,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000,2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd)Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); andLarock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). (all of which are incorporated by reference in their entirety).Other methods for the synthesis of compounds described herein may befound in International Patent Publication No. WO 01/01982901, Arnold etal. Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170;Burchat et al. Bioorganic & Medicinal Chemistry Letters 12 (2002)1687-1690. General methods for the preparation of compound as disclosedherein may be derived from known reactions in the field, and thereactions may be modified by the use of appropriate reagents andconditions, as would be recognized by the skilled person, for theintroduction of the various moieties found in the formulae as providedherein.

The products of the reactions may be isolated and purified, if desired,using conventional techniques, including, but not limited to,filtration, distillation, crystallization, chromatography and the like.Such materials may be characterized using conventional means, includingphysical constants and spectral data.

Compounds described herein may be prepared as a single isomer or amixture of isomers.

Further Forms of Compounds

Compounds disclosed herein have a structure of Formula (IA), (I), (Ia),(II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb). It is understood that whenreference is made to compounds described herein, it is meant to includecompounds of any of Formula (IA), (I), (Ia), (II), (III), (IV),(Va)-(Vh), or (VIa)-(VIb), as well as to all of the specific compoundsthat fall within the scope of these generic formulae, unless otherwiseindicated.

The compounds described herein may possess one or more stereocenters andeach center may exist in the R or S configuration. The compoundspresented herein include all diastereomeric, enantiomeric, and epimericforms as well as the appropriate mixtures thereof. Stereoisomers may beobtained, if desired, by methods known in the art as, for example, theseparation of stereoisomers by chiral chromatographic columns.

Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known, for example, by chromatography and/or fractionalcrystallization. In one embodiment, enantiomers can be separated bychiral chromatographic columns. In other embodiments, enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomers, enantiomers, andmixtures thereof are considered as part of the compositions describedherein.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds described herein, as wellas active metabolites of these compounds having the same type ofactivity. In some situations, compounds may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

Compounds of any of Formula (IA), (I), (Ia), (II), (III), (IV),(Va)-(Vh), or (VIa)-(VIb) in unoxidized form can be prepared fromN-oxides of compounds of any of Formula (IA), (I), (Ia), (II), (III),(IV), (Va)-(Vh), or (VIa)-(VIb) by treating with a reducing agent, suchas, but not limited to, sulfur, sulfur dioxide, triphenyl phosphine,lithium borohydride, sodium borohydride, phosphorus trichloride,tribromide, or the like in a suitable inert organic solvent, such as,but not limited to, acetonitrile, ethanol, aqueous dioxane, or the likeat 0 to 80° C.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound described herein, which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound. To produce a prodrug, apharmaceutically active compound is modified such that the activecompound will be regenerated upon in vivo administration. The prodrugcan be designed to alter the metabolic stability or the transportcharacteristics of a drug, to mask side effects or toxicity, to improvethe flavor of a drug or to alter other characteristics or properties ofa drug. By virtue of knowledge of pharmacodynamic processes and drugmetabolism in vivo, those of skill in this art, once a pharmaceuticallyactive compound is known, can design prodrugs of the compound. (see, forexample, Nogrady (1985) Medicinal Chemistry A Biochemical Approach,Oxford University Press, New York, pages 388-392; Silverman (1992), TheOrganic Chemistry of Drug Design and Drug Action, Academic Press, Inc.,San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic andMedicinal Chemistry Letters, Vol. 4, p. 1985).

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a derivative as set forth herein areincluded within the scope of the claims. In some cases, some of theherein-described compounds may be a prodrug for another derivative oractive compound.

Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. Prodrugs may be designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In some embodiments, the design of a prodrugincreases the effective water solubility. See, e.g., Fedorak et al., Am.J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, all incorporatedherein in their entirety.

Sites on the aromatic ring portion of compounds of any of Formula (IA),(I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb) can besusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, such as, byway of example only, halogens can reduce, minimize or eliminate thismetabolic pathway.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulas and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfer, fluorine and chlorine, suchas ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl, respectively.Certain isotopically-labeled compounds described herein, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Further, substitution with isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formed)by reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, andthe like; or with an organic acid such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; (2) salts formed when anacidic proton present in the parent compound either is replaced by ametal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium),an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion;or coordinates with an organic base. Acceptable organic bases includeethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. Acceptable inorganic bases includealuminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, and the like.

The corresponding counterions of the pharmaceutically acceptable saltsmay be analyzed and identified using various methods including, but notlimited to, ion exchange chromatography, ion chromatography, capillaryelectrophoresis, inductively coupled plasma, atomic absorptionspectroscopy, mass spectrometry, or any combination thereof.

The salts are recovered by using at least one of the followingtechniques: filtration, precipitation with a non-solvent followed byfiltration, evaporation of the solvent, or, in the case of aqueoussolutions, lyophilization.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

It should be understood that a reference to a salt includes the solventaddition forms or crystal forms thereof, particularly solvates orpolymorphs. Solvates contain either stoichiometric or non-stoichiometricamounts of a solvent, and are often formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Polymorphs includethe different crystal packing arrangements of the same elementalcomposition of a compound. Polymorphs usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility.

Various factors such as the recrystallization solvent, rate ofcrystallization, and storage temperature may cause a single crystal formto dominate.

Compounds described herein may be in various forms, including but notlimited to, amorphous forms, milled forms and nano-particulate forms. Inaddition, compounds described herein include crystalline forms, alsoknown as polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability, and solubility. Various factors such as therecrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources.

The various spectroscopic techniques used include, but are not limitedto, Raman, FTIR, UVIS, and NMR (liquid and solid state). The variousmicroscopy techniques include, but are not limited to, polarized lightmicroscopy, Scanning Electron Microscopy (SEM) with Energy DispersiveX-Ray Analysis (EDX), Environmental Scanning Electron Microscopy withEDX (in gas or water vapor atmosphere), IR microscopy, and Ramanmicroscopy.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

Pharmaceutical Composition/Formulation

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. A summary of pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference in their entirety.

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein, such as, for example, compounds of any ofFormula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb),with other chemical components, such as carriers, stabilizers, diluents,dispersing agents, suspending agents, thickening agents, and/orexcipients. The pharmaceutical composition facilitates administration ofthe compound to an organism. In practicing the methods of treatment oruse provided herein, therapeutically effective amounts of compoundsdescribed herein are administered in a pharmaceutical composition to amammal having a disease, disorder, or condition to be treated.Preferably, the mammal is a human. A therapeutically effective amountcan vary widely depending on the severity of the disease, the age andrelative health of the subject, the potency of the compound used andother factors. The compounds can be used singly or in combination withone or more therapeutic agents as components of mixtures.

In certain embodiments, compositions may also include one or more pHadjusting agents or buffering agents, including acids such as acetic,boric, citric, lactic, phosphoric and hydrochloric acids; bases such assodium hydroxide, sodium phosphate, sodium borate, sodium citrate,sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; andbuffers such as citrate/dextrose, sodium bicarbonate and ammoniumchloride. Such acids, bases and buffers are included in an amountrequired to maintain pH of the composition in an acceptable range.

In other embodiments, compositions may also include one or more salts inan amount required to bring osmolality of the composition into anacceptable range. Such salts include those having sodium, potassium orammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compounddescribed herein, such as, for example, a compound of any of Formula(IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), as anactive ingredient in free-acid or free-base form, or in apharmaceutically acceptable salt form. In addition, the methods andpharmaceutical compositions described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), as well asactive metabolites of these compounds having the same type of activity.In some situations, compounds may exist as tautomers. All tautomers areincluded within the scope of the compounds presented herein.Additionally, the compounds described herein can exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The solvated forms of the compoundspresented herein are also considered to be disclosed herein.

“Antifoaming agents” reduce foaming during processing which can resultin coagulation of aqueous dispersions, bubbles in the finished film, orgenerally impair processing. Exemplary anti-foaming agents includesilicon emulsions or sorbitan sesquoleate.

“Antioxidants” include, for example, butylated hydroxytoluene (BHT),sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. Incertain embodiments, antioxidants enhance chemical stability whererequired.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include mercury-containing substances such as merfen andthiomersal; stabilized chlorine dioxide; and quaternary ammoniumcompounds such as benzalkonium chloride, cetyltrimethylammonium bromideand cetylpyridinium chloride.

Formulations described herein may benefit from antioxidants, metalchelating agents, thiol containing compounds and other generalstabilizing agents. Examples of such stabilizing agents, include, butare not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/vmonothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% toabout 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i)heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosanpolysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

“Binders” impart cohesive qualities and include, e.g., alginic acid andsalts thereof, cellulose derivatives such as carboxymethylcellulose,methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®); microcrystalline dextrose; amylose; magnesium aluminumsilicate; polysaccharide acids; bentonites; gelatin;polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone; povidone;starch; pregelatinized starch; tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum suchas acacia, tragacanth, ghatti gum, mucilage of isapol husks,polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone®XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodiumalginate, and the like.

A “carrier” or “carrier materials” include any commonly used excipientsin pharmaceutics and should be selected on the basis of compatibilitywith compounds disclosed herein, such as, compounds of any of Formula(IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), and therelease profile properties of the desired dosage form. Exemplary carriermaterials include, e.g., binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, diluents, and the like. “Pharmaceuticallycompatible carrier materials” may include, but are not limited to,acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate,calcium lactate, maltodextrin, glycerine, magnesium silicate,polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters, sodiumcaseinate, soy lecithin, taurocholic acid, phosphotidylcholine, sodiumchloride, tricalcium phosphate, dipotassium phosphate, cellulose andcellulose conjugates, sugars sodium stearoyl lactylate, carrageenan,monoglyceride, diglyceride, pregelatinized starch, and the like. See,e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999).

“Dispersing agents,” and/or “viscosity modulating agents” includematerials that control the diffusion and homogeneity of a drug throughliquid media or a granulation method or blend method. In someembodiments, these agents also facilitate the effectiveness of a coatingor eroding matrix. Exemplary diffusion facilitators/dispersing agentsinclude, e.g., hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG,polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and thecarbohydrate-based dispersing agents such as, for example, hydroxypropylcelluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M),carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers (e.g., PluronicsF68®, F88®, and F108^(®), which are block copolymers of ethylene oxideand propylene oxide); and poloxamines (e.g., Tetronic 908®, also knownas Poloxamine 908®, which is a tetrafunctional block copolymer derivedfrom sequential addition of propylene oxide and ethylene oxide toethylenediamine (BASF Corporation, Parsippany, N.J.)),polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetatecopolymer (S-630), polyethylene glycol, e.g., the polyethylene glycolcan have a molecular weight of about 300 to about 6000, or about 3350 toabout 4000, or about 7000 to about 5400, sodium carboxymethylcellulose,methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g.,gum tragacanth and gum acacia, guar gum, xanthans, including xanthangum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose,methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodiumalginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitanmonolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates,chitosans and combinations thereof. Plasticizcers such as cellulose ortriethyl cellulose can also be used as dispersing agents. Dispersingagents particularly useful in liposomal dispersions and self-emulsifyingdispersions are dimyristoyl phosphatidyl choline, natural phosphatidylcholine from eggs, natural phosphatidyl glycerol from eggs, cholesteroland isopropyl myristate.

Combinations of one or more erosion facilitator with one or morediffusion facilitator can also be used in the present compositions.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution. In certain embodiments,diluents increase bulk of the composition to facilitate compression orcreate sufficient bulk for homogenous blend for capsule filling. Suchcompounds include e.g., lactose, starch, mannitol, sorbitol, dextrose,microcrystalline cellulose such as Avicel®; dibasic calcium phosphate,dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate;anhydrous lactose, spray-dried lactose; pregelatinized starch,compressible sugar, such as Di-Pac® (Amstar); mannitol,hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetatestearate, sucrose-based diluents, confectioner's sugar; monobasiccalcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactatetrihydrate, dextrates; hydrolyzed cereal solids, amylose; powderedcellulose, calcium carbonate; glycine, kaolin; mannitol, sodiumchloride; inositol, bentonite, and the like.

The term “disintegrate” includes both the dissolution and dispersion ofthe dosage form when contacted with gastrointestinal fluid.“Disintegration agents or disintegrants” facilitate the breakup ordisintegration of a substance. Examples of disintegration agents includea starch, e.g., a natural starch such as corn starch or potato starch, apregelatinized starch such as National 1551 or Amijel®, or sodium starchglycolate such as Promogel® or Explotab®, a cellulose such as a woodproduct, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101,Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, MingTia®, and Solka-Floc®, methylcellulose, croscarmellose, or across-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrosspovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

“Drug absorption” or “absorption” typically refers to the process ofmovement of drug from site of administration of a drug across a barrierinto a blood vessel or the site of action, e.g., a drug moving from thegastrointestinal tract into the portal vein or lymphatic system.

An “enteric coating” is a substance that remains substantially intact inthe stomach but dissolves and releases the drug in the small intestineor colon. Generally, the enteric coating comprises a polymeric materialthat prevents release in the low pH environment of the stomach but thationizes at a higher pH, typically a pH of 6 to 7, and thus dissolvessufficiently in the small intestine or colon to release the active agenttherein.

“Erosion facilitators” include materials that control the erosion of aparticular material in gastrointestinal fluid. Erosion facilitators aregenerally known to those of ordinary skill in the art. Exemplary erosionfacilitators include, e.g., hydrophilic polymers, electrolytes,proteins, peptides, and amino acids.

“Filling agents” include compounds such as lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol,mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

“Flavoring agents” and/or “sweeteners” useful in the formulationsdescribed herein, include, e.g., acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,wintergreen, xylitol, or any combination of these flavoring ingredients,e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon,chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus,orange-cream, vanilla-mint, and mixtures thereof.

“Lubricants” and “glidants” are compounds that prevent, reduce orinhibit adhesion or friction of materials. Exemplary lubricants include,e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, ahydrocarbon such as mineral oil, or hydrogenated vegetable oil such ashydrogenated soybean oil (Sterotex®), higher fatty acids and theiralkali-metal and alkaline earth metal salts, such as aluminum, calcium,magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes,Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol (e.g., PEG-4000) or amethoxypolyethylene glycol such as Carbowax™, sodium oleate, sodiumbenzoate, glyceryl behenate, polyethylene glycol, magnesium or sodiumlauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, a starchsuch as corn starch, silicone oil, a surfactant, and the like.

A “measurable serum concentration” or “measurable plasma concentration”describes the blood serum or blood plasma concentration, typicallymeasured in mg, μg, or ng of therapeutic agent per ml, dl, or 1 of bloodserum, absorbed into the bloodstream after administration. As usedherein, measurable plasma concentrations are typically measured in ng/mlor μg/ml.

“Pharmacodynamics” refers to the factors which determine the biologicresponse observed relative to the concentration of drug at a site ofaction.

“Pharmacokinetics” refers to the factors which determine the attainmentand maintenance of the appropriate concentration of drug at a site ofaction.

“Plasticizers” are compounds used to soften the microencapsulationmaterial or film coatings to make them less brittle. Suitableplasticizers include, e.g., polyethylene glycols such as PEG 300, PEG400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propyleneglycol, oleic acid, triethyl cellulose and triacetin. In someembodiments, plasticizers can also function as dispersing agents orwetting agents.

“Solubilizers” include compounds such as triacetin, triethylcitrate,ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate,vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropylalcohol, cholesterol, bile salts, polyethylene glycol 200-600,glycofurol, transcutol, propylene glycol, and dimethyl isosorbide andthe like.

“Stabilizers” include compounds such as any antioxidation agents,buffers, acids, preservatives and the like.

“Steady state,” as used herein, is when the amount of drug administeredis equal to the amount of drug eliminated within one dosing intervalresulting in a plateau or constant plasma drug exposure.

“Suspending agents” include compounds such as polyvinylpyrrolidone,e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g.,the polyethylene glycol can have a molecular weight of about 300 toabout 6000, or about 3350 to about 4000, or about 7000 to about 5400,sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

“Surfactants” include compounds such as sodium lauryl sulfate, sodiumdocusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Someother surfactants include polyoxyethylene fatty acid glycerides andvegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40. In some embodiments, surfactants may be included toenhance physical stability or for other purposes.

“Viscosity enhancing agents” include, e.g., methyl cellulose, xanthangum, carboxymethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetatestearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinylalcohol, alginates, acacia, chitosans and combinations thereof.

“Wetting agents” include compounds such as oleic acid, glycerylmonostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate,sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium saltsand the like.

Dosage Forms

The compositions described herein can be formulated for administrationto a subject via any conventional means including, but not limited to,oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular),buccal, intranasal, rectal or transdermal administration routes. As usedherein, the term “subject” is used to mean an animal, preferably amammal, including a human or non-human. The terms patient and subjectmay be used interchangeably.

Moreover, the pharmaceutical compositions described herein, whichinclude a compound of any of Formula (IA), (I), (Ia), (II), (III), (IV),(Va)-(Vh), or (VIa)-(VIb) can be formulated into any suitable dosageform, including but not limited to, aqueous oral dispersions, liquids,gels, syrups, elixirs, slurries, suspensions and the like, for oralingestion by a patient to be treated, solid oral dosage forms, aerosols,controlled release formulations, fast melt formulations, effervescentformulations, lyophilized formulations, tablets, powders, pills,dragees, capsules, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate release and controlled releaseformulations.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include, forexample, fillers such as sugars, including lactose, sucrose, mannitol,or sorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder) acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In other embodiments,the pharmaceutical formulation is in the form of a powder. In stillother embodiments, the pharmaceutical formulation is in the form of atablet, including but not limited to, a fast-melt tablet. Additionally,pharmaceutical formulations described herein may be administered as asingle capsule or in multiple capsule dosage form. In some embodiments,the pharmaceutical formulation is administered in two, or three, orfour, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofany of Formula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or(VIa)-(VIb), with one or more pharmaceutical excipients to form a bulkblend composition. When referring to these bulk blend compositions ashomogeneous, it is meant that the particles of the compound of any ofFormula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb),are dispersed evenly throughout the composition so that the compositionmay be readily subdivided into equally effective unit dosage forms, suchas tablets, pills, and capsules. The individual unit dosages may alsoinclude film coatings, which disintegrate upon oral ingestion or uponcontact with diluent. These formulations can be manufactured byconventional pharmacological techniques.

Conventional pharmacological techniques include, e.g., one or acombination of methods: (1) dry mixing, (2) direct compression, (3)milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6)fusion. See, e.g., Lachman et al., The Theory and Practice of IndustrialPharmacy (1986). Other methods include, e.g., spray drying, pan coating,melt granulation, granulation, fluidized bed spray drying or coating(e.g., wurster coating), tangential coating, top spraying, tableting,extruding and the like.

The pharmaceutical solid dosage forms described herein can include acompound described herein and one or more pharmaceutically acceptableadditives such as a compatible carrier, binder, filling agent,suspending agent, flavoring agent, sweetening agent, disintegratingagent, dispersing agent, surfactant, lubricant, colorant, diluent,solubilizer, moistening agent, plasticizer, stabilizer, penetrationenhancer, wetting agent, anti-foaming agent, antioxidant, preservative,or one or more combination thereof. In still other aspects, usingstandard coating procedures, such as those described in Remington'sPharmaceutical Sciences, 20th Edition (2000), a film coating is providedaround the formulation of the compound of any of Formula (IA), (I),(Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb). In one embodiment,some or all of the particles of the compound of any of Formula (IA),(I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), are coated. Inanother embodiment, some or all of the particles of the compound of anyof Formula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or(VIa)-(VIb), are microencapsulated. In still another embodiment, theparticles of the compound of any of Formula (IA), (I), (Ia), (II),(III), (IV), (Va)-(Vh), or (VIa)-(VIb), are not microencapsulated andare uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound of any of Formula (IA), (I), (Ia),(II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), from a solid dosage formmatrix as efficiently as possible, disintegrants are often used in theformulation, especially when the dosage forms are compressed withbinder.

Disintegrants help rupturing the dosage form matrix by swelling orcapillary action when moisture is absorbed into the dosage form.Suitable disintegrants for use in the solid dosage forms describedherein include, but are not limited to, natural starch such as cornstarch or potato starch, a pregelatinized starch such as National 1551or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, acellulose such as a wood product, methylcrystalline cellulose, e.g.,Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100,Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose,croscarmellose, or a cross-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that canbe filled into soft or hard shell capsules and for tablet formulation,they ensure the tablet remaining intact after compression and helpassure blend uniformity prior to a compression or fill step. Materialssuitable for use as binders in the solid dosage forms described hereininclude, but are not limited to, carboxymethylcellulose, methylcellulose(e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USPPharmacoat-603, hydroxypropylmethylcellulose acetate stearate (AqoateHS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g.,Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystallinecellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesiumaluminum silicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. Formulators skilled in art can determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

The term “non water-soluble diluent” represents compounds typically usedin the formulation of pharmaceuticals, such as calcium phosphate,calcium sulfate, starches, modified starches and microcrystallinecellulose, and microcellulose (e.g., having a density of about 0.45g/cm³, e.g. Avicel, powdered cellulose), and talc.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol can have a molecular weight of about 300 to about6000, or about 3350 to about 4000, or about 7000 to about 5400, vinylpyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

It should be appreciated that there is considerable overlap betweenadditives used in the solid dosage forms described herein. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in solid dosageforms described herein. The amounts of such additives can be readilydetermined by one skilled in the art, according to the particularproperties desired.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of the compound of any of Formula (IA), (I), (Ia), (II), (III),(IV), (Va)-(Vh), or (VIa)-(VIb), from the formulation. In otherembodiments, the film coating aids in patient compliance (e.g., Opadry®coatings or sugar coating). Film coatings including Opadry® typicallyrange from about 1% to about 3% of the tablet weight. In otherembodiments, the compressed tablets include one or more excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound of any of Formula (IA), (I), (Ia), (II),(III), (IV), (Va)-(Vh), or (VIa)-(VIb), described above, inside of acapsule. In some embodiments, the formulations (non-aqueous suspensionsand solutions) are placed in a soft gelatin capsule. In otherembodiments, the formulations are placed in standard gelatin capsules ornon-gelatin capsules such as capsules comprising HPMC. In otherembodiments, the formulation is placed in a sprinkle capsule, whereinthe capsule may be swallowed whole or the capsule may be opened and thecontents sprinkled on food prior to eating. In some embodiments, thetherapeutic dose is split into multiple (e.g., two, three, or four)capsules. In some embodiments, the entire dose of the formulation isdelivered in a capsule form.

In various embodiments, the particles of the compound of any of Formula(IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), and oneor more excipients are dry blended and compressed into a mass, such as atablet, having a hardness sufficient to provide a pharmaceuticalcomposition that substantially disintegrates within less than about 30minutes, less than about 35 minutes, less than about 40 minutes, lessthan about 45 minutes, less than about 50 minutes, less than about 55minutes, or less than about 60 minutes, after oral administration,thereby releasing the formulation into the gastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with compounds of any of Formula (IA), (I), (Ia),(II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), which sufficiently isolatethe compound of any of Formula (IA), (I), (Ia), (II), (III), (IV),(Va)-(Vh), or (VIa)-(VIb), from other non-compatible excipients.Materials compatible with compounds of any of Formula (IA), (I), (Ia),(II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), are those that delay therelease of the compounds of any of Formula (IA), (I), (Ia), (II), (III),(IV), (Va)-(Vh), or (VIa)-(VIb), in vivo.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including compounds described herein, include, butare not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel®or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such asE461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5,Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols,e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,stearic acid, propylene glycol, oleic acid, and triacetin areincorporated into the microencapsulation material. In other embodiments,the microencapsulating material useful for delaying the release of thepharmaceutical compositions is from the USP or the National Formulary(NF). In yet other embodiments, the microencapsulation material isKlucel. In still other embodiments, the microencapsulation material ismethocel.

Microencapsulated compounds of any of Formula (IA), (I), (Ia), (II),(III), (IV), (Va)-(Vh), or (VIa)-(VIb), may be formulated by methodsknown by one of ordinary skill in the art. Such known methods include,e.g., spray drying processes, spinning disk-solvent processes, hot meltprocesses, spray chilling methods, fluidized bed, electrostaticdeposition, centrifugal extrusion, rotational suspension separation,polymerization at liquid-gas or solid-gas interface, pressure extrusion,or spraying solvent extraction bath. In addition to these, severalchemical techniques, e.g., complex coacervation, solvent evaporation,polymer-polymer incompatibility, interfacial polymerization in liquidmedia, in situ polymerization, in-liquid drying, and desolvation inliquid media could also be used. Furthermore, other methods such asroller compaction, extrusion/spheronization, coacervation, ornanoparticle coating may also be used.

In one embodiment, the particles of compounds of any of Formula (IA),(I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), aremicroencapsulated prior to being formulated into one of the above forms.In still another embodiment, some or most of the particles are coatedprior to being further formulated by using standard coating procedures,such as those described in Remington's Pharmaceutical Sciences, 20thEdition (2000).

In other embodiments, the solid dosage formulations of the compounds ofany of Formula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or(VIa)-(VIb), are plasticized (coated) with one or more layers.Illustratively, a plasticizer is generally a high boiling point solid orliquid. Suitable plasticizers can be added from about 0.01% to about 50%by weight (w/w) of the coating composition. Plasticizers include, butare not limited to, diethyl phthalate, citrate esters, polyethyleneglycol, glycerol, acetylated glycerides, triacetin, polypropyleneglycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearicacid, stearol, stearate, and castor oil.

In other embodiments, a powder including the formulations with acompound of any of Formula (IA), (I), (Ia), (II), (III), (IV),(Va)-(Vh), or (VIa)-(VIb), described herein, may be formulated toinclude one or more pharmaceutical excipients and flavors. Such a powdermay be prepared, for example, by mixing the formulation and optionalpharmaceutical excipients to form a bulk blend composition. Additionalembodiments also include a suspending agent and/or a wetting agent. Thisbulk blend is uniformly subdivided into unit dosage packaging ormulti-dosage packaging units.

In still other embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When salts of the compositions describedherein are added to water, the acids and the base react to liberatecarbon dioxide gas, thereby causing “effervescence.” Examples ofeffervescent salts include, e.g., the following ingredients: sodiumbicarbonate or a mixture of sodium bicarbonate and sodium carbonate,citric acid and/or tartaric acid. Any acid-base combination that resultsin the liberation of carbon dioxide can be used in place of thecombination of sodium bicarbonate and citric and tartaric acids, as longas the ingredients were suitable for pharmaceutical use and result in apH of about 6.0 or higher.

In other embodiments, the formulations described herein, which include acompound of Formula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or(VIa)-(VIb), are solid dispersions. Methods of producing such soliddispersions are known in the art and include, but are not limited to,for example, U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485,5,723,269, and U.S. Pub. Appl 2004/0013734, each of which isspecifically incorporated by reference. In still other embodiments, theformulations described herein are solid solutions. Solid solutionsincorporate a substance together with the active agent and otherexcipients such that heating the mixture results in dissolution of thedrug and the resulting composition is then cooled to provide a solidblend which can be further formulated or directly added to a capsule orcompressed into a tablet. Methods of producing such solid solutions areknown in the art and include, but are not limited to, for example, U.S.Pat. Nos. 4,151,273, 5,281,420, and 6,083,518, each of which isspecifically incorporated by reference.

The pharmaceutical solid oral dosage forms including formulationsdescribed herein, which include a compound of any of Formula (IA), (I),(Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), can be furtherformulated to provide a controlled release of the compound of Formula(IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb).Controlled release refers to the release of the compound of any ofFormula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb),from a dosage form in which it is incorporated according to a desiredprofile over an extended period of time. Controlled release profilesinclude, for example, sustained release, prolonged release, pulsatilerelease, and delayed release profiles. In contrast to immediate releasecompositions, controlled release compositions allow delivery of an agentto a subject over an extended period of time according to apredetermined profile. Such release rates can provide therapeuticallyeffective levels of agent for an extended period of time and therebyprovide a longer period of pharmacologic response while minimizing sideeffects as compared to conventional rapid release dosage forms. Suchlonger periods of response provide for many inherent benefits that arenot achieved with the corresponding short acting, immediate releasepreparations.

In some embodiments, the solid dosage forms described herein can beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. The enteric coated dosage formmay be a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release can be accomplished at some generally predictable locationin the intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. In someembodiments the method for delay of release is coating. Any coatingsshould be applied to a sufficient thickness such that the entire coatingdoes not dissolve in the gastrointestinal fluids at pH below about 5,but does dissolve at pH about 5 and above. It is expected that anyanionic polymer exhibiting a pH-dependent solubility profile can be usedas an enteric coating in the methods and compositions described hereinto achieve delivery to the lower gastrointestinal tract. In someembodiments the polymers described herein are anionic carboxylicpolymers. In other embodiments, the polymers and compatible mixturesthereof, and some of their properties, include, but are not limited to:

Shellac, also called purified lac, a refined product obtained from theresinous secretion of an insect. This coating dissolves in media ofpH>7;

Acrylic polymers. The performance of acrylic polymers (primarily theirsolubility in biological fluids) can vary based on the degree and typeof substitution. Examples of suitable acrylic polymers includemethacrylic acid copolymers and ammonium methacrylate copolymers.

The Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are availableas solubilized in organic solvent, aqueous dispersion, or dry powders.The Eudragit series RL, NE, and RS are insoluble in the gastrointestinaltract but are permeable and are used primarily for colonic targeting.The Eudragit series E dissolve in the stomach. The Eudragit series L,L-30D and S are insoluble in stomach and dissolve in the intestine;

Cellulose Derivatives. Examples of suitable cellulose derivatives are:ethyl cellulose; reaction mixtures of partial acetate esters ofcellulose with phthalic anhydride. The performance can vary based on thedegree and type of substitution. Cellulose acetate phthalate (CAP)dissolves in pH>6. Aquateric (FMC) is an aqueous based system and is aspray dried CAP psuedolatex with particles <1 μm. Other components inAquateric can include pluronics, Tweens, and acetylated monoglycerides.Other suitable cellulose derivatives include: cellulose acetatetrimellitate (Eastman); methylcellulose (Pharmacoat, Methocel);hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetatesuccinate (e.g., AQOAT (Shin Etsu)). The performance can vary based onthe degree and type of substitution. For example, HPMCP such as, HP-50,HP-55, HP-55S, HP-55F grades are suitable. The performance can varybased on the degree and type of substitution. For example, suitablegrades of hydroxypropylmethylcellulose acetate succinate include, butare not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF),which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.These polymers are offered as granules, or as fine powders for aqueousdispersions;

Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH>5, and it ismuch less permeable to water vapor and gastric fluids.

In some embodiments, the coating can, and usually does, contain aplasticizer and possibly other coating excipients such as colorants,talc, and/or magnesium stearate, which are well known in the art.Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin(glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate,acetylated monoglycerides, glycerol, fatty acid esters, propyleneglycol, and dibutyl phthalate. In particular, anionic carboxylic acrylicpolymers usually will contain 10-25% by weight of a plasticizer,especially dibutyl phthalate, polyethylene glycol, triethyl citrate andtriacetin. Conventional coating techniques such as spray or pan coatingare employed to apply coatings. The coating thickness must be sufficientto ensure that the oral dosage form remains intact until the desiredsite of topical delivery in the intestinal tract is reached.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants(e.g., carnuba wax or PEG) may be added to the coatings besidesplasticizers to solubilize or disperse the coating material, and toimprove coating performance and the coated product.

In other embodiments, the formulations described herein, which include acompound of Formula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or(VIa)-(VIb), are delivered using a pulsatile dosage form. A pulsatiledosage form is capable of providing one or more immediate release pulsesat predetermined time points after a controlled lag time or at specificsites. Pulsatile dosage forms including the formulations describedherein, which include a compound of any of Formula (IA), (I), (Ia),(II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), may be administered usinga variety of pulsatile formulations known in the art. For example, suchformulations include, but are not limited to, those described in U.S.Pat. Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329, each of whichis specifically incorporated by reference. Other pulsatile releasedosage forms suitable for use with the present formulations include, butare not limited to, for example, U.S. Pat. Nos. 4,871,549, 5,260,068,5,260,069, 5,508,040, 5,567,441 and 5,837,284, all of which arespecifically incorporated by reference. In one embodiment, thecontrolled release dosage form is pulsatile release solid oral dosageform including at least two groups of particles, (i.e. multiparticulate)each containing the formulation described herein. The first group ofparticles provides a substantially immediate dose of the compound of anyof Formula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or(VIa)-(VIb), upon ingestion by a mammal. The first group of particlescan be either uncoated or include a coating and/or sealant. The secondgroup of particles includes coated particles, which includes from about2% to about 75%, from about 2.5% to about 70%, or from about 40% toabout 70%, by weight of the total dose of the compound of any of Formula(IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), in saidformulation, in admixture with one or more binders. The coating includesa pharmaceutically acceptable ingredient in an amount sufficient toprovide a delay of from about 2 hours to about 7 hours followingingestion before release of the second dose. Suitable coatings includeone or more differentially degradable coatings such as, by way ofexample only, pH sensitive coatings (enteric coatings) such as acrylicresins (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30DEudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100,Eudragit® E100, Eudragit® L12.5, Eudragit® S 12.5, and Eudragit® NE30D,Eudragit® NE 40D®) either alone or blended with cellulose derivatives,e.g., ethylcellulose, or non-enteric coatings having variable thicknessto provide differential release of the formulation that includes acompound of any of Formula (IA), (I), (Ia), (II), (III), (IV),(Va)-(Vh), or (VIa)-(VIb).

Many other types of controlled release systems known to those ofordinary skill in the art and are suitable for use with the formulationsdescribed herein. Examples of such delivery systems include, e.g.,polymer-based systems, such as polylactic and polyglycolic acid,plyanhydrides and polycaprolactone; porous matrices, nonpolymer-basedsystems that are lipids, including sterols, such as cholesterol,cholesterol esters and fatty acids, or neutral fats, such as mono-, di-and triglycerides; hydrogel release systems; silastic systems;peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using conventional binders and the like. See, e.g.,Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214(1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2^(nd)Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509,5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410,5,977,175, 6,465,014 and 6,932,983, each of which is specificallyincorporated by reference.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of the compounds of any of Formula (IA), (I), (Ia),(II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), described herein and atleast one dispersing agent or suspending agent for oral administrationto a subject. The formulations may be a powder and/or granules forsuspension, and upon admixture with water, a substantially uniformsuspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2^(nd) Ed., pp. 754-757(2002). In addition to the particles of compound of Formula (IA), (I),(Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), the liquid dosageforms may include additives, such as: (a) disintegrating agents; (b)dispersing agents; (c) wetting agents; (d) at least one preservative,(e) viscosity enhancing agents, (f) at least one sweetening agent, and(g) at least one flavoring agent. In some embodiments, the aqueousdispersions can further include a crystalline inhibitor.

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

Examples of disintegrating agents for use in the aqueous suspensions anddispersions include, but are not limited to, a starch, e.g., a naturalstarch such as corn starch or potato starch, a pregelatinized starchsuch as National 1551 or Amijel®, or sodium starch glycolate such asPromogel® or Explotab®; a cellulose such as a wood product,methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel PH102,Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, andSolka-Floc®, methylcellulose, croscarmellose, or a cross-linkedcellulose, such as cross-linked sodium carboxymethylcellulose(Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linkedcroscarmellose; a cross-linked starch such as sodium starch glycolate; across-linked polymer such as crospovidone; a cross-linkedpolyvinylpyrrolidone; alginate such as alginic acid or a salt of alginicacid such as sodium alginate; a clay such as Veegum® HV (magnesiumaluminum silicate); a gum such as agar, guar, locust bean, Karaya,pectin, or tragacanth; sodium starch glycolate; bentonite; a naturalsponge; a surfactant; a resin such as a cation-exchange resin; citruspulp; sodium lauryl sulfate; sodium lauryl sulfate in combinationstarch; and the like.

In some embodiments, the dispersing agents suitable for the aqueoussuspensions and dispersions described herein are known in the art andinclude, for example, hydrophilic polymers, electrolytes, Tween® 60 or80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®),and the carbohydrate-based dispersing agents such as, for example,hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMCK100M), carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate,hydroxypropylmethyl-cellulose acetate stearate, noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone®,e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethyleneoxide and formaldehyde (also known as tyloxapol), poloxamers (e.g.,Pluronics F68®, F88®, and F108®, which are block copolymers of ethyleneoxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, alsoknown as Poloxamine 908®, which is a tetrafunctional block copolymerderived from sequential addition of propylene oxide and ethylene oxideto ethylenediamine (BASF Corporation, Parsippany, N.J.)). In otherembodiments, the dispersing agent is selected from a group notcomprising one of the following agents: hydrophilic polymers;electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP);hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M,and Pharmacoat® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium;methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulosephthalate; hydroxypropylmethyl-cellulose acetate stearate;non-crystalline cellulose; magnesium aluminum silicate; triethanolamine;polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®,F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); or poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®).

Wetting agents suitable for the aqueous suspensions and dispersionsdescribed herein are known in the art and include, but are not limitedto, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fattyacid esters (e.g., the commercially available Tweens® such as e.g.,Tween 20® and Tween 80((ICI Specialty Chemicals)), and polyethyleneglycols (e.g., Carbowaxs 3350® and 1450®, and Carbopol 934® (UnionCarbide)), oleic acid, glyceryl monostearate, sorbitan monooleate,sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitanmonooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodiumlauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodiumtaurocholate, simethicone, phosphotidylcholine and the like

Suitable preservatives for the aqueous suspensions or dispersionsdescribed herein include, for example, potassium sorbate, parabens(e.g., methylparaben and propylparaben), benzoic acid and its salts,other esters of parahydroxybenzoic acid such as butylparaben, alcoholssuch as ethyl alcohol or benzyl alcohol, phenolic compounds such asphenol, or quaternary compounds such as benzalkonium chloride.Preservatives, as used herein, are incorporated into the dosage form ata concentration sufficient to inhibit microbial growth.

Suitable viscosity enhancing agents for the aqueous suspensions ordispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, Plasdon® S-630, carbomer,polyvinyl alcohol, alginates, acacia, chitosans and combinationsthereof. The concentration of the viscosity enhancing agent will dependupon the agent selected and the viscosity desired.

Examples of sweetening agents suitable for the aqueous suspensions ordispersions described herein include, for example, acacia syrup,acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream,berry, black currant, butterscotch, calcium citrate, camphor, caramel,cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citruspunch, citrus cream, cotton candy, cocoa, cola, cool cherry, coolcitrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose,fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup,grape, grapefruit, honey, isomalt, lemon, lime, lemon cream,monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple,marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet®Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol,spearmint, spearmint cream, strawberry, strawberry cream, stevia,sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfamepotassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose,tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wildcherry, wintergreen, xylitol, or any combination of these flavoringingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint,menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. Inone embodiment, the aqueous liquid dispersion can comprise a sweeteningagent or flavoring agent in a concentration ranging from about 0.001% toabout 1.0% the volume of the aqueous dispersion. In another embodiment,the aqueous liquid dispersion can comprise a sweetening agent orflavoring agent in a concentration ranging from about 0.005% to about0.5% the volume of the aqueous dispersion. In yet another embodiment,the aqueous liquid dispersion can comprise a sweetening agent orflavoring agent in a concentration ranging from about 0.01% to about1.0% the volume of the aqueous dispersion.

In addition to the additives listed above, the liquid formulations canalso include inert diluents commonly used in the art, such as water orother solvents, solubilizing agents, and emulsifiers. Exemplaryemulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propyleneglycol,1,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodiumdoccusate, cholesterol, cholesterol esters, taurocholic acid,phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corngerm oil, olive oil, castor oil, and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters ofsorbitan, or mixtures of these substances, and the like.

In some embodiments, the pharmaceutical formulations described hereincan be self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase can beadded just prior to administration, which ensures stability of anunstable or hydrophobic active ingredient. Thus, the SEDDS provides aneffective delivery system for oral and parenteral delivery ofhydrophobic active ingredients. SEDDS may provide improvements in thebioavailability of hydrophobic active ingredients. Methods of producingself-emulsifying dosage forms are known in the art and include, but arenot limited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and6,960,563, each of which is specifically incorporated by reference.

It is to be appreciated that there is overlap between the above-listedadditives used in the aqueous dispersions or suspensions describedherein, since a given additive is often classified differently bydifferent practitioners in the field, or is commonly used for any ofseveral different functions. Thus, the above-listed additives should betaken as merely exemplary, and not limiting, of the types of additivesthat can be included in formulations described herein. The amounts ofsuch additives can be readily determined by one skilled in the art,according to the particular properties desired.

Intranasal Formulations

Intranasal formulations are known in the art and are described in, forexample, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452, each ofwhich is specifically incorporated by reference. Formulations thatinclude a compound of any of Formula (IA), (I), (Ia), (II), (III), (IV),(Va)-(Vh), or (VIa)-(VIb), which are prepared according to these andother techniques well-known in the art are prepared as solutions insaline, employing benzyl alcohol or other suitable preservatives,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, for example, Ansel, H. C. et al., Pharmaceutical DosageForms and Drug Delivery Systems, Sixth Ed. (1995). Preferably thesecompositions and formulations are prepared with suitable nontoxicpharmaceutically acceptable ingredients. These ingredients are known tothose skilled in the preparation of nasal dosage forms and some of thesecan be found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21stedition, 2005, a standard reference in the field. The choice of suitablecarriers is highly dependent upon the exact nature of the nasal dosageform desired, e.g., solutions, suspensions, ointments, or gels. Nasaldosage forms generally contain large amounts of water in addition to theactive ingredient. Minor amounts of other ingredients such as pHadjusters, emulsifiers or dispersing agents, preservatives, surfactants,gelling agents, or buffering and other stabilizing and solubilizingagents may also be present. The nasal dosage form should be isotonicwith nasal secretions.

For administration by inhalation, the compounds of any of Formula (IA),(I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), describedherein may be in a form as an aerosol, a mist or a powder.Pharmaceutical compositions described herein are conveniently deliveredin the form of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, such as, by way of example only, gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compounddescribed herein and a suitable powder base such as lactose or starch.

Buccal Formulations

Buccal formulations that include compounds of any of Formula (IA), (I),(Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), may be administeredusing a variety of formulations known in the art. For example, suchformulations include, but are not limited to, U.S. Pat. Nos. 4,229,447,4,596,795, 4,755,386, and 5,739,136, each of which is specificallyincorporated by reference. In addition, the buccal dosage formsdescribed herein can further include a bioerodible (hydrolysable)polymeric carrier that also serves to adhere the dosage form to thebuccal mucosa. The buccal dosage form is fabricated so as to erodegradually over a predetermined time period, wherein the delivery of thecompound of any of Formula (IA), (I), (Ia), (II), (III), (IV),(Va)-(Vh), or (VIa)-(VIb), is provided essentially throughout. Buccaldrug delivery, as will be appreciated by those skilled in the art,avoids the disadvantages encountered with oral drug administration,e.g., slow absorption, degradation of the active agent by fluids presentin the gastrointestinal tract and/or first-pass inactivation in theliver. With regard to the bioerodible (hydrolysable) polymeric carrier,it will be appreciated that virtually any such carrier can be used, solong as the desired drug release profile is not compromised, and thecarrier is compatible with the compound of any of Formula (IA), (I),(Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), and any othercomponents that may be present in the buccal dosage unit. Generally, thepolymeric carrier comprises hydrophilic (water-soluble andwater-swellable) polymers that adhere to the wet surface of the buccalmucosa. Examples of polymeric carriers useful herein include acrylicacid polymers and co, e.g., those known as “carbomers” (Carbopol®, whichmay be obtained from B.F. Goodrich, is one such polymer). Othercomponents may also be incorporated into the buccal dosage formsdescribed herein include, but are not limited to, disintegrants,diluents, binders, lubricants, flavoring, colorants, preservatives, andthe like. For buccal or sublingual administration, the compositions maytake the form of tablets, lozenges, or gels formulated in a conventionalmanner.

Transdermal Formulations

Transdermal formulations described herein may be administered using avariety of devices which have been described in the art. For example,such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122,3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636,3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084,4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303,5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and6,946,144, each of which is specifically incorporated by reference inits entirety.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiments, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound ofany of Formula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or(VIa)-(VIb); (2) a penetration enhancer; and (3) an aqueous adjuvant. Inaddition, transdermal formulations can include additional componentssuch as, but not limited to, gelling agents, creams and ointment bases,and the like. In some embodiments, the transdermal formulation canfurther include a woven or non-woven backing material to enhanceabsorption and prevent the removal of the transdermal formulation fromthe skin. In other embodiments, the transdermal formulations describedherein can maintain a saturated or supersaturated state to promotediffusion into the skin.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds of any of Formula (IA),(I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb). The rate ofabsorption can be slowed by using rate-controlling membranes or bytrapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Injectable Formulations

Formulations that include a compound of any of Formula (IA), (I), (Ia),(II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb), suitable forintramuscular, subcutaneous, or intravenous injection may includephysiologically acceptable sterile aqueous or non-aqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents,solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art. For other parenteral injections, appropriateformulations may include aqueous or nonaqueous solutions, preferablywith physiologically compatible buffers or excipients. Such excipientsare generally known in the art.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

Other Formulations

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. Suchpharmaceutical compounds can contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Examples of Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the inhibition of Btk or a homolog thereof, or for thetreatment of diseases or conditions that would benefit, at least inpart, from inhibition of Btk or a homolog thereof. In addition, a methodfor treating any of the diseases or conditions described herein in asubject in need of such treatment, involves administration ofpharmaceutical compositions containing at least one compound of any ofFormula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb),described herein, or a pharmaceutically acceptable salt,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, in therapeutically effective amounts to said subject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. It is considered well within the skill of theart for one to determine such therapeutically effective amounts byroutine experimentation (including, but not limited to, a doseescalation clinical trial).

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. It is considered well within theskill of the art for one to determine such prophylactically effectiveamounts by routine experimentation (e.g., a dose escalation clinicaltrial). When used in a patient, effective amounts for this use willdepend on the severity and course of the disease, disorder or condition,previous therapy, the patient's health status and response to the drugs,and the judgment of the treating physician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from 10%-100%,including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be routinelydetermined in a manner known in the art according to the particularcircumstances surrounding the case, including, e.g., the specific agentbeing administered, the route of administration, the condition beingtreated, and the subject or host being treated. In general, however,doses employed for adult human treatment will typically be in the rangeof 0.02-5000 mg per day, or from about 1-1500 mg per day. The desireddose may conveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The foregoing ranges are merely suggestive, as the number of variablesin regard to an individual treatment regime is large, and considerableexcursions from these recommended values are not uncommon. Such dosagesmay be altered depending on a number of variables, not limited to theactivity of the compound used, the disease or condition to be treated,the mode of administration, the requirements of the individual subject,the severity of the disease or condition being treated, and the judgmentof the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Treatments

The reversible or irreversible Btk inhibitor compositions describedherein can also be used in combination with other well known therapeuticreagents that are selected for their therapeutic value for the conditionto be treated. In general, the compositions described herein and, inembodiments where combinational therapy is employed, other agents do nothave to be administered in the same pharmaceutical composition, and may,because of different physical and chemical characteristics, have to beadministered by different routes. The determination of the mode ofadministration and the advisability of administration, where possible,in the same pharmaceutical composition, is well within the knowledge ofthe skilled clinician. The initial administration can be made accordingto established protocols known in the art, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the skilled clinician.

In certain instances, it may be appropriate to administer at least onereversible or irreversible Btk inhibitor compound described herein incombination with another therapeutic agent. By way of example only, ifone of the side effects experienced by a patient upon receiving one ofthe reversible or irreversible Btk inhibitor compounds described hereinis nausea, then it may be appropriate to administer an anti-nausea agentin combination with the initial therapeutic agent. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may have minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, by way of example only, the benefitexperienced by a patient may be increased by administering one of thecompounds described herein with another therapeutic agent (which alsoincludes a therapeutic regimen) that also has therapeutic benefit. Inany case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may simply beadditive of the two therapeutic agents or the patient may experience asynergistic benefit.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds may beadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compounds used. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the skilledphysician after evaluation of the disease being treated and thecondition of the patient.

It is known to those of skill in the art that therapeutically-effectivedosages can vary when the drugs are used in treatment combinations.Methods for experimentally determining therapeutically-effective dosagesof drugs and other agents for use in combination treatment regimens aredescribed in the literature. For example, the use of metronomic dosing,i.e., providing more frequent, lower doses in order to minimize toxicside effects, has been described extensively in the literatureCombination treatment further includes periodic treatments that startand stop at various times to assist with the clinical management of thepatient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof Formula (IA), (I), (Ia), (II), (III), (IV), (Va)-(Vh), or (VIa)-(VIb)described herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may vary from more than zero weeks to less than fourweeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents; theuse of multiple therapeutic combinations are also envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder from which the subject suffers, as well as the age, weight,sex, diet, and medical condition of the subject. Thus, the dosageregimen actually employed can vary widely and therefore can deviate fromthe dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The compounds and compositionscan be administered to a subject during or as soon as possible after theonset of the symptoms. The administration of the compounds can beinitiated within the first 48 hours of the onset of the symptoms, withinthe first 6 hours of the onset of the symptoms, or within 3 hours of theonset of the symptoms. The initial administration can be via any routepractical, such as, for example, an intravenous injection, a bolusinjection, infusion over 5 minutes to about 5 hours, a pill, a capsule,transdermal patch, buccal delivery, and the like, or combinationthereof. A compound should be administered as soon as is practicableafter the onset of a disease or condition is detected or suspected, andfor a length of time necessary for the treatment of the disease, suchas, for example, from about 1 month to about 3 months. The length oftreatment can vary for each subject, and the length can be determinedusing the known criteria. For example, the compound or a formulationcontaining the compound can be administered for at least 2 weeks,between about 1 month to about 5 years, or from about 1 month to about 3years.

Exemplary Therapeutic Agents for Use in Combination with a Reversible orIrreversible Btk Inhibitor Compound

Where the subject is suffering from or at risk of suffering from anautoimmune disease, an inflammatory disease, or an allergy disease, areversible or irreversible Btk inhibitor compound can be used in withone or more of the following therapeutic agents in any combination:immunosuppressants (e.g., tacrolimus, cyclosporin, rapamicin,methotrexate, cyclophosphamide, azathioprine, mercaptopurine,mycophenolate, or FTY720), glucocorticoids (e.g., prednisone, cortisoneacetate, prednisolone, methylprednisolone, dexamethasone, betamethasone,triamcinolone, beclometasone, fludrocortisone acetate,deoxycorticosterone acetate, aldosterone), non-steroidalanti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, orsulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,celecoxib, or rofecoxib), leflunomide, gold thioglucose, goldthiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline,TNF-α binding proteins (e.g., infliximab, etanercept, or adalimumab),abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergyvaccines, antihistamines, antileukotrienes, beta-agonists, theophylline,or anticholinergics.

Where the subject is suffering from or at risk of suffering from aB-cell proliferative disorder (e.g., plasma cell myeloma), the subjectedcan be treated with a reversible or irreversible Btk inhibitor compoundin any combination with one or more other anti-cancer agents. In someembodiments, one or more of the anti-cancer agents are proapoptoticagents. Examples of anti-cancer agents include, but are not limited to,any of the following: gossyphol, genasense, polyphenol E, Chlorofusin,all trans-retinoic acid (ATRA), bryostatin, tumor necrosisfactor-related apoptosis-inducing ligand (TRAIL),5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352,Taxol™, also referred to as “paclitaxel”, which is a well-knownanti-cancer drug which acts by enhancing and stabilizing microtubuleformation, and analogs of Taxol™, such as Taxotere™. Compounds that havethe basic taxane skeleton as a common structure feature, have also beenshown to have the ability to arrest cells in the G2-M phases due tostabilized microtubules and may be useful for treating cancer incombination with the compounds described herein.

Further examples of anti-cancer agents for use in combination with areversible or irreversible Btk inhibitor compound include inhibitors ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies(e.g., rituxan).

Other anti-cancer agents that can be employed in combination with areversible or irreversible Btk inhibitor compound include Adriamycin,Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine;interleukin II (including recombinant interleukin II, or rlL2),interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-1 a; interferon gamma-1 b; iproplatin;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide;safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestoloneacetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

Other anti-cancer agents that can be employed in combination with areversible or irreversible Btk inhibitor compound include: 20-epi-1, 25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B 1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Yet other anticancer agents that can be employed in combination with areversible or irreversible Btk inhibitor compound include alkylatingagents, antimetabolites, natural products, or hormones, e.g., nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.),alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,lomusitne, ete.), or triazenes (decarbazine, etc.). Examples ofantimetabolites include but are not limited to folic acid analog (e.g.,methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs(e.g., mercaptopurine, thioguanine, pentostatin).

Examples of natural products useful in combination with a reversible orirreversible Btk inhibitor compound include but are not limited to vincaalkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g.,etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin),enzymes (e.g., L-asparaginase), or biological response modifiers (e.g.,interferon alpha).

Examples of alkylating agents that can be employed in combination areversible or irreversible Btk inhibitor compound include, but are notlimited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, ete.). Examples of antimetabolitesinclude, but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

Examples of hormones and antagonists useful in combination with areversible or irreversible Btk inhibitor compound include, but are notlimited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),gonadotropin releasing hormone analog (e.g., leuprolide). Other agentsthat can be used in the methods and compositions described herein forthe treatment or prevention of cancer include platinum coordinationcomplexes (e.g., cisplatin, carboblatin), anthracenedione (e.g.,mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazinederivative (e.g., procarbazine), adrenocortical suppressant (e.g.,mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with a reversible or irreversible Btk inhibitor compoundinclude without limitation the following marketed drugs and drugs indevelopment: Erbulozole (also known as R-55104), Dolastatin 10 (alsoknown as DLS-10 and NSC-376128), Mivobulin isethionate (also known asCI-980), Vincristine, NSC-639829, Discodermolide (also known asNVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins(such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such asSpongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, andSpongistatin 9), Cemadotin hydrochloride (also known as LU-103793 andNSC-D-669356), Epothilones (such as Epothilone A, Epothilone B,Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D(also referred to as KOS-862, dEpoB, and desoxyepothilone B), EpothiloneE, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide,16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705),21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF),26-fluoroepothilone), Auristatin PE (also known as NSC-654663),Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known asLS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477(Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristinesulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known asWS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy ofSciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651),SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97(Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko),IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739(Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto,also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A),Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known asNSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 andTI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 andWHI-261), H10 (Kansas State University), H16 (Kansas State University),Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker HughesInstitute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute),SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine(also known as NSC-698666), 3-lAABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411(Sanofi).

Where the subject is suffering from or at risk of suffering from athromboembolic disorder (e.g., stroke), the subject can be treated witha reversible or irreversible Btk inhibitor compound in any combinationwith one or more other anti-thromboembolic agents. Examples ofanti-thromboembolic agents include, but are not limited any of thefollowing: thrombolytic agents (e.g., alteplase anistreplase,streptokinase, urokinase, or tissue plasminogen activator), heparin,tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xainhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a,otamixaban, LY517717, or YM150), ticlopidine, clopidogrel, CS-747(prasugrel, LY640315), ximelagatran, or BIBR 1048.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits can includea carrier, package, or container that is compartmentalized to receiveone or more containers such as vials, tubes, and the like, each of thecontainer(s) including one of the separate elements to be used in amethod described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers can be formedfrom a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment. A wide array of formulations ofthe compounds and compositions provided herein are contemplated as are avariety of treatments for any disease, disorder, or condition that wouldbenefit by inhibition of Btk, or in which Btk is a mediator orcontributor to the symptoms or cause.

For example, the container(s) can include one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically may include one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

In certain embodiments, the pharmaceutical compositions can be presentedin a pack or dispenser device which can contain one or more unit dosageforms containing a compound provided herein. The pack can for examplecontain metal or plastic foil, such as a blister pack. The pack ordispenser device can be accompanied by instructions for administration.The pack or dispenser can also be accompanied with a notice associatedwith the container in form prescribed by a governmental agencyregulating the manufacture, use, or sale of pharmaceuticals, whichnotice is reflective of approval by the agency of the form of the drugfor human or veterinary administration. Such notice, for example, can bethe labeling approved by the U.S. Food and Drug Administration forprescription drugs, or the approved product insert. Compositionscontaining a compound provided herein formulated in a compatiblepharmaceutical carrier can also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition.

EXAMPLES

The following specific and non-limiting examples are to be construed asmerely illustrative, and do not limit the present disclosure in any waywhatsoever. Without further elaboration, it is believed that one skilledin the art can, based on the description herein, utilize the presentdisclosure to its fullest extent. All publications cited herein arehereby incorporated by reference in their entirety. Where reference ismade to a URL or other such identifier or address, it is understood thatsuch identifiers can change and particular information on the internetcan come and go, but equivalent information can be found by searchingthe internet. Reference thereto evidences the availability and publicdissemination of such information.

Example 1: Synthesis of(E)-4-(6-amino-9-(3-(4-(dimethylamino)-N-methylbut-2-enamido)phenyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)-N-(pyridin-2-yl)benzamide(6)

To ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (1) (350mg, 1.50 mmol) in acetonitrile (10 mL) was added methyl 4-aminobenzoate(340 mg, 2.25 mmol) and then diisopropylethylamine (DIEA, 0.39 mL, 2.25mmol). The mixture was stirred at RT for 3 h. To the mixture was thenadded ammonia (7.0 N solution in methanol, 30 mL). The mixture wasstirred overnight. The solid was isolated by filtration, washed with aminimum amount of cold acetonitrile and then washed with hexane. Thesolid was dried in a vacuum oven to afford methyl4-(6-carbamoyl-3-(methylthio)-1,2,4-triazin-5-ylamino)benzoate (2) (348mg, 73% yield) in high purity.

To a solution of 2 (200 mg, 0.62 mmol) in NMP (10 mL) was added addedmCPBA (77% strength, 420 mg, 1.86 mmol). The mixture was stirred at RTfor 1 h. To the mixture was added DIEA (0.52 mL, 3.00 mmol) and(R)-(3-BOC-amino)piperidine (3) (240 mg, 1.20 mmol). The mixture wasstirred at 90° C. for 90 min. The mixture was cooled, diluted with 200mL EtOAc, washed with 1N NaOH and brine, dried, and concentrated invacuo. The residue was subjected to flash column chromatography with 0to 30% EtOAc in DCM to yield (R)-methyl4-(3-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-6-carbamoyl-1,2,4-triazin-5-ylamino)benzoate(4) in quantitative yield.

To a solution of 4 in MeOH (10 mL), water (10 mL) and THF (40 mL) at RTwas added LiOH hydrate (126 mg, 3.0 mmol). The mixture was stirredovernight. The mixture was concentrated in vacuo, acidified with HCl(until pH -2), and extracted with EtOAc (×3). The organic extracts werecombined, dried and concentrated in vacuo to dryness to yield(R)-4-(3-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-6-carbamoyl-1,2,4-triazin-5-ylamino)benzoicacid (5) in quantitative yield.

Compound 5 (90 mg, 0.20 mmol) was mixed with morpholine (53 μL, 0.60mmol) in DMF (5 mL). To the mixture were added DIEA (105 μL, 0.60 mmol)and PyBOP (312 mg, 0.60 mmol). The mixture was stirred for 5 min,diluted with 100 mL EtOAc, washed with brine ×2, dried, and concentratedin vacuo. The residue was subjected to flash column chromatography with50 to 100% EtOAc in hexane to isolate (R)-tert-butyl1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-ylcarbamatein quantitative yield. (R)-tert-butyl1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-ylcarbamatewas treated with DCM (10 mL) and TFA (3 mL) for 1 h at RT. The mixturewas concentrated in vacuo to dryness. The residue was subjected toreverse phase prep HPLC to isolate the(R)-3-(3-aminopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(6) as HCl salt. MS found for C₂₀H₂₆N₈O₃ as (M+H)⁺ 427.1, (M−H)⁻ 425.2.UV: λ=270 nm.

Example 2: Synthesis of(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(7)

To a solution of 6 HCl salt (46 mg, 0.10 mmol) in NMP (2 mL) was addedDIEA (70 μL, 0.40 mmol) and then 4-tert-butylbenzoyl chloride (39 mg,0.20 mmol). The mixture was stirred at RT for 45 min, quenched with TFA(0.1 mL), diluted with water (2 mL), and subjected to reverse phase prepHPLC to afford(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(7) (27 mg) as HCl salt. MS found for C₃₁H₃₈N₈O₄ as (M+H)⁺ 587.2, (M−H)⁻585.4. UV: λ=273 nm.

Example 3: Synthesis of(R)-3-(3-(4-tert-butyl-N-methylbenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(11)

To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (8)(6.27 g, 33.5 mmol) in DCM (100 mL) was added DIEA (8.75 mL, 50.3 mmol)and then 4-tert-butylbenzoyl chloride (8.0 mL, 43.6 mmol) in drop-wisemanner. The mixture was stirred for 3 h at RT, diluted with DCM, washedwith 1N NaOH, dried, and concentrated. The residue was subjected toflash column chromatography with 0 to 10% EtOAc in DCM to give(R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (11.0g, 91%). To a solution of (R)-tert-butyl3-(4-tert-butylbenzamido)piperidine-1-carboxylate (850 mg, 2.36 mmol) inDMF (10 mL) was added NaH (60% in mineral oil, 190 mg, 4.72 mmol). Themixture was stirred at RT for 10 min and then iodomethane (0.44 mL, 7.08mmol) was added. The mixture was stirred at RT for 1 h, and diluted with150 mL EtOAc. The mixture was washed with water ×2, dried, andconcentrated. The residue was subjected to flash column with 0 to 3%MeOH in DCM to afford (R)-tert-butyl3-(4-tert-butyl-N-methylbenzamido)piperidine-1-carboxylate (9) inquantitative yield. It was treated with 15 mL 4N HCl in dioxane at RTfor 1 h. The mixture was concentrated in vacuo to dryness to afford(R)-4-tert-butyl-N-methyl-N-(piperidin-3-yl)benzamide (10) HCl salt inquantitative yield.

To a solution of3-(methylthio)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(75 mg, 0.20 mmol) in NMP (5 mL) was added mCPBA (77% strength, 150 mg,0.60 mmol). The mixture was stirred at RT for 1 h to yield a mixture ofcorresponding sulfone and sulfoxide. To the mixture was added DIEA (0.35mL, 2.00 mmol) and 10 (125 mg, 0.40 mmol). The mixture was stirred at90° C. for 90 min. The mixture was cooled, diluted with 100 mL EtOAc,washed with 1N NaOH and brine, dried, and concentrated in vacuo. Theresidue was subjected to flash column chromatography with 0 to 5% MeOHin DCM and further purified using reverse phase preparative HPLC toyield the title compound (11) as HCl salt (100 mg). MS found forC₃₂H₄₀N₈O₄ as (M+H)⁺ 601.3, (M−H)⁻ 599.3. UV: λ=277 nm.

Example 4: Synthesis of(R)-3-(3-(4-methylbenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(12)

To a solution of 6 HCl salt (90 mg, 0.19 mmol) in DMF (3 mL) was addedDIEA (135 μL, 0.76 mmol) and then p-toluoyl chloride (50 μL, 0.38 mmol).The mixture was stirred at RT for 30 min, diluted with 100 mL EtOAc,washed with water, dried, and concentrated. The residue was subjected toflash column chromatography with 0 to 7% MeOH in DCM to isolate thetitle compound (12) (61 mg). MS found for C₂₈H₃₂N₈O₄ as (M+H)⁺ 545.2,(M−H)⁻ 543.2. UV: λ=272 nm.

Example 5: Synthesis of(R)-3-(3-benzamidopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(13)

In a similar manner as described in Example 4,(R)-3-(3-benzamidopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(13) was prepared using benzoyl chloride. MS found for C₂₇H₃₀N₈O₄ as(M+H)⁺ 531.1, (M−H)⁻ 529.3. UV: λ=274 nm.

Example 6: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(4-(trifluoromethyl)benzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(14)

In a similar manner as described in Example 4,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(4-(trifluoromethyl)benzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(14) was prepared using 3-trifluoromethylbenzoyl chloride. MS found forC₂₈H₂₉F₃N₈O₄ as (M+H)⁺ 599.1, (M−H)⁻ 597.2. UV: λ=275 nm.

Example 7: Synthesis of(R)-3-(3-(4-cyanobenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(15)

In a similar manner as described in Example 4,(R)-3-(3-(4-cyanobenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(15) was prepared using 4-cyanobenzoyl chloride. MS found for C₂₈H₂₉N₉O₄as (M+H)⁺ 556.2, (M−H)⁻ 554.3. UV: λ=272 nm.

Example 8: Synthesis of(R)-3-(3-(4-chlorobenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(16)

In a similar manner as described in Example 4,(R)-3-(3-(4-chlorobenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(16) was prepared using 4-chlorobenzoyl chloride. MS found forC₂₇H₂₉ClN₈O₄ as (M+H)⁺ 565.1 (chloro pattern), (M−H)⁻ 563.2 (chloropattern). UV: λ=272 nm.

Example 9: Synthesis of(R)-3-(3-(4-fluorobenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(17)

In a similar manner as described in Example 4,(R)-3-(3-(4-fluorobenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(17) was prepared using 4-fluorobenzoyl chloride. MS found forC₂₇H₂₉FN₈O₄ as (M+H)⁺ 549.2, (M−H)⁻ 547.3. UV: λ=274 nm.

Example 10: Synthesis of(R)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(18)

To a solution of 6 (65 mg, 0.14 mmol) in DMF (3 mL) was added p-anisicacid (43 mg, 0.28 mmol), DIEA (200 μL, 1.12 mmol) and then PyBOP (150mg, 0.28 mmol). The mixture was stirred at RT for 1 h, acidified withTFA (0.3 mL), diluted with water (2 mL), and subjected to reverse phasepreparative HPLC to isolate the title compound (18) (55 mg) as HCl salt.MS found for C₂₈H₃₂N₈O₅ as (M+H)⁺ 561.2, (M−H)⁻ 559.3. UV: λ=261 nm.

Example 11: Synthesis of(R)-3-(3-(4-cyclopropylbenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(19)

In a similar manner as described in Example 10,(R)-3-(3-(4-cyclopropylbenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(19) was prepared using 4-cyclopropylbenzoic acid. MS found forC₃₀H₃₄N₈O₄ as (M+H)⁺ 571.2, (M−H)⁻ 569.3. UV: λ=260 nm.

Example 12: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(picolinamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(20)

In a similar manner as described in Example 10,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(picolinamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(20) was prepared using picolinic acid. MS found C₂₆H₂₉N₉O₄ as (M+H)⁺532.2, (M−H)⁻ 530.3. UV: λ=269 nm.

Example 13: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(nicotinamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(21)

In a similar manner as described in Example 10,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(nicotinamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(21) was prepared using nicotinic acid. MS found C₂₆H₂₉N₉O₄ as (M+H)⁺532.1, (M−H)⁻ 530.3. UV: λ=269 nm.

Example 14: Synthesis of(R)-3-(3-(isonicotinamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(22)

In a similar manner as described in Example 10,(R)-3-(3-(isonicotinamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(22) was prepared using isonicotinic acid. MS found C₂₆H₂₉N₉O₄ as (M+H)⁺532.2, (M−H)⁻ 530.3. UV: λ=270 nm.

Example 15: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(pyrimidine-2-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(23)

In a similar manner as described in Example 10,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(pyrimidine-2-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(23) was prepared using pyrimidine-2-carboxylic acid. MS foundC₂₅H₂₈N₁₀O₄ as (M+H)⁺ 533.2, (M−H)⁻ 531.2. UV: λ=271 nm.

Example 16: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)thiazole-2-carboxamide(24)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)thiazole-2-carboxamide(24) was prepared using thiazole-2-carboxylic acid. MS found C₂₄H₂₇N₉O₄Sas (M+H)⁺ 538.2, (M−H)⁻ 536.2. UV: λ=275 nm.

Example 17: Synthesis of(R)-3-(3-(5-chlorothiophene-2-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(25)

In a similar manner as described in Example 10,(R)-3-(3-(5-chlorothiophene-2-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(25) was prepared using 5-chlorothiophene-2-carboxylic acid. MS foundC₂₅H₂₇ClN₈O₄S as (M+H)⁺ 570.1, (M−H)⁻ 569.2. UV: λ=278 nm.

Example 18: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)quinoline-3-carboxamide(26)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)quinoline-3-carboxamide(26) was prepared using quinoline-3-carboxylic acid. MS found C₃₀H₃₁N₉O₄as (M+H)⁺ 582.2, (M−H)⁻ 580.3. UV: λ=277 nm.

Example 19: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide(27)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide(27) was prepared using imidazo[1,2-a]pyridine-6-carboxylic acid. MSfound C₂₈H₃₀N₁₀O₄ as (M+H)⁺ 571.2, (M−H)⁻ 569.3. UV: λ=276 nm.

Example 20: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-7-carboxamide(28)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-7-carboxamide(28) was prepared using imidazo[1,2-a]pyridine-7-carboxylic acid. MSfound C₂₈H₃₀N₁₀O₄ as (M+H)⁺ 571.2, (M−H)⁻ 569.3. UV: λ=281 nm.

Example 21: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-propionamidopiperidin-1-yl)-1,2,4-triazine-6-carboxamide(29)

In a similar manner as described in Example 4,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-propionamidopiperidin-1-yl)-1,2,4-triazine-6-carboxamide(29) was prepared using propionyl chloride. MS found for C₂₃H₃₀N₈O₄ as(M+H)⁺ 483.1, (M−H)⁻ 481.2. UV: λ=275 nm.

Example 22: Synthesis of(R)-3-(3-acrylamidopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(30)

In a similar manner as described in Example 4,(R)-3-(3-acrylamidopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(30) was prepared using acryloyl chloride. MS found for C₂₃H₂₈N₈O₄ as(M+H)⁺ 481.1, (M−H)⁻ 479.3. UV: λ=274 nm.

Example 23: Synthesis of(R)-3-(3-but-2-ynamidopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(31)

In a similar manner as described in Example 10,(R)-3-(3-but-2-ynamidopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(31) was prepared using but-2-ynoic acid. MS found C₂₄H₂₈N₈O₄ as (M+H)⁺493.1, (M−H)⁻ 491.2. UV: λ=274 nm.

Example 24: Synthesis of(R)-3-(3-isobutyramidopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(32)

In a similar manner as described in Example 4,(R)-3-(3-isobutyramidopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(32) was prepared using isobutyryl chloride. MS found for C₂₄H₃₂N₈O₄ as(M+H)⁺ 497.2, (M−H)⁻ 495.3. UV: λ=275 nm.

Example 25: Synthesis of(R)-3-(3-(cyclopropanecarboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(33)

In a similar manner as described in Example 4,(R)-3-(3-(cyclopropanecarboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(33) was prepared using cyclopropanecarbonyl chloride. MS found forC₂₄H₃₀N₈O₄ as (M+H)⁺ 495.1, (M−H)⁻ 493.3. UV: λ=275 nm.

Example 26: Synthesis of(R)-3-(3-(cyclobutanecarboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(34)

In a similar manner as described in Example 10,(R)-3-(3-(cyclobutanecarboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(34) was prepared using cyclobutanecarboxylic acid. MS found forC₂₅H₃₂N₈O₄ as (M+H)⁺ 509.1, (M−H)⁻ 507.3. UV: λ=276 nm.

Example 27: Synthesis of(R)-3-(3-(2-cyanoacetamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(35)

In a similar manner as described in Example 10,(R)-3-(3-(2-cyanoacetamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(35) was prepared using 2-cyanoacetic acid. MS found for C₂₃H₂₇N₉O₄ as(M+H)⁺ 494.1, (M−H)⁻ 492.2. UV: λ=275 nm.

Example 28: Synthesis of(R)-3-(3-(1-cyanocyclopropanecarboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(36)

In a similar manner as described in Example 10,(R)-3-(3-(1-cyanocyclopropanecarboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(36) was prepared using 1-cyanocyclopropanecarboxylic acid. MS found forC₂₅H₂₉N₉O₄ as (M+H)⁺ 520.2, (M−H)⁻ 518.2. UV: λ=276 nm.

Example 29: Synthesis of(R)-3-(3-(cyclopentanecarboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(37)

In a similar manner as described in Example 4,(R)-3-(3-(cyclopentanecarboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(37) was prepared using cyclopentanecarbonyl chloride. MS found forC₂₆H₃₄N₈O₄ as (M+H)⁺ 523.2, (M−H)⁻521.3. UV: λ=276 nm.

Example 30: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(tetrahydro-2H-pyran-4-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(38)

In a similar manner as described in Example 10,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(tetrahydro-2H-pyran-4-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(38) was prepared using tetrahydro-2H-pyran-4-carboxylic acid. MS foundfor C₂₆H₃₄N₈O₅ as (M+H)⁺ 539.2, (M−H)⁻ 537.3. UV: λ=275 nm.

Example 31: Synthesis of(R)-3-(3-(1-methylpiperidine-4-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(39)

In a similar manner as described in Example 10,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(tetrahydro-2H-pyran-4-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(39) was prepared using 1-methylpiperidine-4-carboxylic acid. MS foundfor C₂₇H₃₇N₉O₄ as (M+H)⁺ 552.2, (M−H)⁻ 550.3. UV: λ=276 nm.

Example 32: Synthesis of(R)-3-(3-(1-cyclopropylpiperidine-4-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(40)

In a similar manner as described in Example 10,(R)-3-(3-(1-cyclopropylpiperidine-4-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(40) was prepared using 1-cyclopropylpiperidine-4-carboxylic acid. MSfound for C₂₉H₃₉N₉O₄ as (M+H)⁺ 578.2, (M−H)⁻ 576.3. UV: λ=276 nm.

Example 33: Synthesis of(R)-3-(3-(1-cyclopentylpiperidine-4-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(41)

In a similar manner as described in Example 10,(R)-3-(3-(1-cyclopentylpiperidine-4-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(41) was prepared using 1-cyclopentylpiperidine-4-carboxylic acid. MSfound for C₃₁H₄₃N₉O₄ as (M+H)⁺ 606.3, (M−H)⁻ 604.4. UV: λ=276 nm.

Example 34: Synthesis of(R)-3-(3-(1-acetylpiperidine-4-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(42)

In a similar manner as described in Example 10,(R)-3-(3-(1-acetylpiperidine-4-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(42) was prepared using 1-acetylpiperidine-4-carboxylic acid. MS foundfor C₂₈H₃₇N₉O₅ as (M+H)⁺ 580.2, (M−H)⁻ 578.3. UV: λ=275 nm.

Example 35: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(pyrrolidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(43)

In a similar manner as described in Example 4,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(pyrrolidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(43) was prepared using 1-pyrrolidinecarbonyl chloride. MS found forC₂₅H₃₃N₉O₄ as (M+H)⁺ 524.2, (M−H)⁻ 522.3. UV: λ=275 nm.

Example 36: Synthesis of(R)-3-(3-(1-acetylpiperidine-4-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(44)

In a similar manner as described in Example 4,(R)-3-(3-(1-acetylpiperidine-4-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(44) was prepared using 1-piperidinecarbonyl chloride. MS found forC₂₆H₃₅N₉O₄ as (M+H)⁺ 538.2, (M−H)⁻ 536.3. UV: λ=276 nm.

Example 37: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-1,4′-bipiperidine-1′-carboxamide(45)

In a similar manner as described in Example 4,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-1,4′-bipiperidine-1′-carboxamide(45) was prepared using 4-piperidinopiperidine-1-carbonyl chloride. MSfound for C₃₁H₄₄N₁₀O₄ as (M+H)⁺ 621.2, (M−H)⁻ 619.4. UV: λ=277 nm.

Example 38: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)morpholine-4-carboxamide(46)

In a similar manner as described in Example 4,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)morpholine-4-carboxamide(46) was prepared using morpholine-4-carbonyl chloride. MS found forC₂₅H₃₃N₉O₅ as (M+H)⁺ 540.2, (M−H)⁻ 538.3. UV: λ=275 nm.

Example 39: Synthesis of(R)-3-(3-(3-methyl-3-phenylureido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(47)

In a similar manner as described in Example 4,(R)-3-(3-(3-methyl-3-phenylureido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(47) was prepared using N-methyl-N-phenylcarbamoyl chloride. MS foundfor C₂₈H₃₃N₉O₄ as (M+H)⁺ 560.2, (M−H)⁻ 558.3. UV: λ=279 nm.

Example 40: Synthesis of(R)-3-(3-(cyclopropanesulfonamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(48)

In a similar manner as described in Example 4,(R)-3-(3-(cyclopropanesulfonamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(48) was prepared using cyclopropanesulfonyl chloride. MS found forC₂₃H₃₀N₈O₅S as (M+H)⁺ 519.1, (M−H)⁻ 517.2. UV: λ=275 nm.

Example 41: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(phenylsulfonamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(49)

In a similar manner as described in Example 4,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(phenylsulfonamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (49) wasprepared using benzenesulfonyl chloride. MS found for C₂₆H₃₀N₈O₅S as(M+H)⁺ 567.1, (M−H)⁻ 565.2. UV: λ=273 nm.

Example 42: Synthesis of(R)-3-(3-(isopropylamino)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(50)

To a solution of(R)-3-(3-aminopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamideHCl salt (100 mg, 0.21 mmol) in 1,2-dichloroethane (10 mL) and dioxane(10 mL) was added DIEA (0.18 mL, 1.05 mmol) and then acetone (0.31 mL,4.2 mmol). The mixture was stirred for 3 h at RT. To the mixture wasadded HOAc (0.12 mL, 2.1 mmol) and then NaBH(OAc)₃ (223 mg, 1.05 mmol).The mixture was stirred at RT overnight and then water (2 mL) was added.The mixture was concentrated in vacuo and subjected to reverse phasepreparative HPLC to afford the title compound as HCl salt (50) (17 mg).MS found for C₂₃H₃₂N₈O₃ as (M+H)⁺ 469.2, (M−H)⁻ 467.3. UV: λ=268 nm.

Example 43: Synthesis of(R)-3-(3-(cyclopentylamino)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(51)

In a similar manner as described in Example 42,(R)-3-(3-(cyclopentylamino)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(51) was prepared using cyclopentanone. MS found for C₂₅H₃₄N₈O₃ as(M+H)⁺ 495.2, (M−H)⁻ 493.3. UV: λ=270 nm.

Example 44: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(2-oxopyrrolidin-1-yl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(52)

To a solution of(R)-3-(3-aminopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamideHCl salt (6) (90 mg, 0.19 mmol) in NMP (3 mL) was added DIEA (0.27 mL,1.52 mmol) and then 3-bromopropanoyl chloride (108 mg, 0.58 mmol). Themixture was stirred at RT for 1 h and then at 60° C. for 1 h. Themixture was cooled to RT, diluted with EtOAc, washed with water andconcentrated in vacuo to afford crude(R)-3-(3-(4-chlorobutanamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide.To a solution of(R)-3-(3-(4-chlorobutanamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamidein DMF (3 mL) was added NaH (60% in mineral oil, 30 mg, 0.75 mmol). Themixture was stirred at RT for 1 h. The mixture was diluted with water,acidified with TFA, and subjected to reverse phase preparative HPLC toisolate the title compound (52) as HCl salt (31 mg). MS found forC₂₄H₃₀N₈O₄ as (M+H)⁺ 495.1, (M−H)⁻ 493.2. UV: λ=275 nm.

Example 45: Synthesis of(R)-3-(3-(isoquinolin-1-yloxy)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(55)

A mixture of 1-hydroxyisoquinoline (1.00 g, 6.9 mmol),(S)-1-BOC-3-hydroxypiperidine (4.17 g, 20.7 mmol), Ph₃P (7.23 g, 27.6mmol) in THF (40 mL) was stirred at RT into a clear solution. DIAD (5.43mL, 27.6 mmol) was added dropwise. The mixture was stirred at RT for 1 hand then at 50° C. for overnight. The mixture was diluted with EtOAc,washed with water ×3, dried, and concentrated in vacuo. The residue wassubjected to flash column chromatography with 0% to 15% EtOAc in DCM toafford (R)-tert-butyl 3-(isoquinolin-1-yloxy)piperidine-1-carboxylate(53).

Compound 53 was treated with 4N HCl in dioxane (40 mL) at RT for 3 h.The mixture was concentrated in vacuo to give a viscous oil which wasdissolved in MeCN (200 mL). To the solution was added NaHCO₃powder (2.0g). The mixture was stirred at RT overnight. The mixture was filteredand the filtrate was concentrated. The residue was subjected to flashcolumn chromatography with 0%-100% EtOAc in DCM and then 0%-9% MeOH inDCM to isolate (R)-1-(piperidin-3-yloxy)isoquinoline (54).

To a solution of3-(methylthio)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(75 mg, 0.20 mmol) in NMP (4 mL) was added mCPBA (77% strength, 140 mg,0.60 mmol). The mixture was stirred at RT for 30 m to yield a mixture ofcorresponding sulfone and sulfoxide. To the mixture was then added DIEA(0.28 mL, 1.60 mmol) and Compound 54 (100 mg, 0.40 mmol). The mixturewas heated at 90° C. for 90 min. The mixture was cooled, diluted withEtOAc (100 mL), washed with 1N NaOH and brine, dried, and concentratedin vacuo. The residue was subjected to flash column chromatography with50 to 100% EtOAc in DCM and further subjected to reverse phasepreparative HPLC to afford the title compound (55) as an HCl salt (45mg). MS found for C₂₉H₃₀N₈O₄ as (M+H)⁺ 555.2, (M−H)⁻ 553.3. UV: λ=275nm.

Example 46: Synthesis of (R)-diisopropyl1-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)hydrazine-1,2-dicarboxylate(56)

The title compound (56) was isolated as a by-product from the final-stepreaction mixture during synthetic preparation of(R)-3-(3-(isoquinolin-1-yloxy)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(55) as an HCl salt using reverse phase preparative HPLC. MS found forC₂₈H₃₉N₉O₇ as (M+H)⁺ 614.2, (M−H)⁻ 612.3. UV: λ=277 nm.

Example 47: Synthesis of(R)-3-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(60)

A mixture of 6-cyclopropyl-8-fluoroisoquinolin-1-ol (500 mg, 2.46 mmol),(S)-1-BOC-3-hydroxypiperidine (1.49 g, 7.39 mmol), Ph₃P (2.58 g, 9.84mmol) in THF (20 mL) was stirred at RT into a clear solution. DIAD (1.94mL, 9.84 mmol) was added dropwise. The mixture was stirred at RT for 48h. The mixture was diluted with EtOAc, washed with water ×3, dried, andconcentrated in vacuo. The residue was subjected to flash columnchromatography with 0% to 5% EtOAc in DCM to afford (R)-tert-butyl3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)piperidine-1-carboxylate(57) as minor product and (R)-tert-butyl3-(6-cyclopropyl-8-fluoroisoquinolin-1-yloxy)piperidine-1-carboxylate asmajor product (58).

Compound 57 was treated with 4N HCl in dioxane (20 mL) at RT for 1 h.The mixture was concentrated in vacuo and the solid residue wastriturated with MTBE (40 mL) at RT overnight. The solid was filtered,washed with MTBE and dried in vacuo to give(R)-6-cyclopropyl-8-fluoro-2-(piperidin-3-yl)isoquinolin-1(2H)-onehydrochloride (59) (51 mg).

In a similar manner as described in Example 3,(R)-3-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(60) was prepared using(R)-6-cyclopropyl-8-fluoro-2-(piperidin-3-yl)isoquinolin-1(2H)-onehydrochloride (59). MS found for C₃₂H₃₃FN₈₀O₄ as (M+H)⁺ 613.1, (M−H)⁻611.3. UV: λ=246, 267, 274, 323, 328 nm.

Example 48: Synthesis of(R)-3-(3-(6-cyclopropyl-8-fluoroisoquinolin-1-yloxy)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(62)

In a similar manner as described in Example 47,(R)-3-(3-(6-cyclopropyl-8-fluoroisoquinolin-1-yloxy)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(62) was prepared using (R)-tert-butyl3-(6-cyclopropyl-8-fluoroisoquinolin-1-yloxy)piperidine-1-carboxylate(58). MS found for C₃₂H₃₃FN₈O₄ as (M+H)⁺ 613.2, (M−H)⁻ 611.3. UV: λ=282nm.

Example 49: Synthesis of(R)-3-(3-(4-tert-butylbenzamido)pyrrolidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(63)

In a similar manner as described in Example 4,(R)-3-(3-(4-tert-butylbenzamido)pyrrolidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(63) was prepared using (R)-3-BOC-aminopyrrolidine and4-tert-butylbenzoyl chloride. MS found for C₃₀H₃₆N₈O₄ as (M+H)⁺ 573.2,(M−H)⁻ 571.4. UV: λ=244 nm.

Example 50: Synthesis of(R)-3-(3-benzamidopyrrolidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(64)

In a similar manner as described in Example 5,(R)-3-(3-benzamidopyrrolidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(64) was prepared using (R)-3-BOC-aminopyrrolidine. MS found forC₂₆H₂₈N₈O₄ as (M+H)⁺ 517.1, (M−H)⁻ 515.2. UV: λ=238, 247, 268, 270 nm.

Example 51: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(2,2,2-trifluoroacetamido)pyrrolidin-1-yl)-1,2,4-triazine-6-carboxamide(65)

In a similar manner as described in Example 4,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(2,2,2-trifluoroacetamido)pyrrolidin-1-yl)-1,2,4-triazine-6-carboxamide(65) was prepared using (R)-3-BOC-aminopyrrolidine and trifluoroacetylchloride. MS found for C₂₁H₂₃F₃N₈O₄ as (M+H)⁺ 509.1, (M−H)⁻ 507.2. UV:λ=239, 275 nm.

Example 52: Synthesis of(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(5-fluoropyridin-3-ylamino)-1,2,4-triazine-6-carboxamide(66)

In a similar manner as described in Example 4,(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(5-fluoropyridin-3-ylamino)-1,2,4-triazine-6-carboxamide(66) was prepared using 3-amino-5-fluoropyridine and 4-tert-butylbenzoylchloride. MS found for C25H29FN8O2 as (M+H)⁺ 493.2, (M−H)⁻ 491.3. UV:λ=259, 323, 343 nm.

Example 53: Synthesis of(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(p-tolylamino)-1,2,4-triazine-6-carboxamide(67)

In a similar manner as described in Example 4,(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(p-tolylamino)-1,2,4-triazine-6-carboxamide(67) was prepared using p-toluidine and 4-tert-butylbenzoyl chloride. MSfound for C₂₇H₃₃N₇O₂ as (M+H)⁺ 488.2, (M−H)⁻ 486.3. UV: λ=240, 248, 256,322, 347 nm.

Example 54: Synthesis of(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(m-tolylamino)-1,2,4-triazine-6-carboxamide(68)

In a similar manner as described in Example 4,(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(m-tolylamino)-1,2,4-triazine-6-carboxamide(68) was prepared using m-toluidine and 4-tert-butylbenzoyl chloride. MSfound for C₂₇H₃₃N₇O₂ as (M+H)⁺ 488.2, (M−H)⁻ 486.3. UV: λ=258, 319, 347nm.

Example 55: Synthesis of(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide(69)

In a similar manner as described in Example 4,(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide(69) was prepared using 4-methylsulfonylaniline and 4-tert-butylbenzoylchloride. MS found for C₂₇H₃₃N₇O₄S as (M+H)⁺ 552.2, (M−H)⁻ 550.3. UV:λ=283 nm.

Example 56: Synthesis of(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(4-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide(70)

In a similar manner as described in Example 4,(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(4-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide(70) was prepared using 4-(pyrimidin-2-yl)aniline and4-tert-butylbenzoyl chloride. MS found for C₃₀H₃₃N₉O₂ as (M+H)⁺ 522.2,(M−H)⁻ 550.3. UV: λ=260, 313 nm.

Example 57: Synthesis of(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(3-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide(71)

In a similar manner as described in Example 4,(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(3-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide(71) was prepared using 3-(pyrimidin-2-yl)aniline and4-tert-butylbenzoyl chloride. MS found for C₃₀H₃₃N₉O₂ as (M+H)⁺ 522.2,(M−H)⁻ 550.3. UV: λ=259, 331, 334 nm.

Example 58: Synthesis of(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(4-(oxazol-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide(72)

In a similar manner as described in Example 4,(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(4-(oxazol-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide(72) was prepared using 4-(oxazol-2-yl)aniline and 4-tert-butylbenzoylchloride. MS found for C₂₉H₃₂N₈O₃ as (M+H)⁺ 541.2, (M−H)⁻ 539.3. UV:λ=311 nm.

Example 59: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(oxazol-2-yl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)morpholine-4-carboxamide(73)

In a similar manner as described in Example 4,(R)-N-(1-(6-carbamoyl-5-(4-(oxazol-2-yl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)morpholine-4-carboxamide(73) was prepared using 4-(oxazol-2-yl)aniline and morpholine-4-carbonylchloride. MS found for C₂₃H₂₇N₉O₄ as (M+H)⁺ 494.2, (M−H)⁻ 492.2. UV:λ=310 nm.

Example 60: Synthesis of (R)-tert-butyl3-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-ylamino)piperidine-1-carboxylate(74)

To a solution of3-(methylthio)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(170 mg, 0.46 mmol) in NMP (20 mL) was added mCPBA (77% strength, 310mg, 1.38 mmol). The mixture was stirred at RT for 1 h to yield a mixtureof corresponding sulfone and sulfoxide. To the mixture was then addedadded DIEA (0.40 mL, 2.30 mmol) and (R)-tert-butyl3-aminopiperidine-1-carboxylate (184 mg, 0.92 mmol). The mixture washeated at 90° C. for 90 m. The mixture was cooled, diluted with 300 mLEtOAc, washed with 1N NaOH and brine, dried, and concentrated in vacuo.The residue was subjected to flash column chromatography with 0 to 6%MeOH in DCM to yield the title compound (74) (210 mg, 87% yield). MSfound C₂₅H₃₄N₈O₅ as (M+H)⁺ 527.2, (M−H)⁻ 525.3. UV: λ=252, 267, 283 nm.

Example 61: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(piperidin-3-ylamino)-1,2,4-triazine-6-carboxamide(75)

(R)-tert-butyl3-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-ylamino)piperidine-1-carboxylate(74) (180 mg) was treated with 4N HCl in dioxane (30 mL) at RT for 3 h.The mixture was concentrated in vacuo to yield the title compound (75)as HCl salt in quantitative yield. MS found C₂₀H₂₆N₈O₃ as (M+H)⁺ 427.1,(M−H)⁻ 425.2. UV: λ=264, 283 nm.

Example 62: Synthesis of(R)-3-(1-(4-tert-butylbenzoyl)piperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(76)

To a solution of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(piperidin-3-ylamino)-1,2,4-triazine-6-carboxamide(75) HCl salt (60 mg, 0.13 mmol) in NMP (3 mL) was added DIEA (90 μL,0.76 mmol) and then 4-tert-butylbenzoyl chloride (39 mg, 0.20 mmol). Themixture was stirred at RT for 20 min, quenched with TFA (0.1 mL),diluted with 2 mL water, and subjected to reverse phase preparative HPLCto afford the title compound (76) as an HCl salt. MS found forC₃₁H₃₈N₈O₄ as (M+H)⁺ 587.2, (M−H)⁻ 585.2. UV: λ=268, 287 nm.

Example 63: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(1-propionylpiperidin-3-ylamino)-1,2,4-triazine-6-carboxamide(77)

In a similar manner as described in Example 62,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(1-propionylpiperidin-3-ylamino)-1,2,4-triazine-6-carboxamide(77) was prepared using propionyl chloride. MS found for C₂₃H₃₀N₈O₄ as(M+H)⁺ 483.2, (M−H)⁻ 481.3. UV: λ=243, 268, 279 nm.

Example 64: Synthesis of(R)-3-(1-(cyclopropanecarbonyl)piperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(78)

In a similar manner as described in Example 62,(R)-3-(1-(cyclopropanecarbonyl)piperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(78) was prepared using cyclopropanecarbonyl chloride. MS found forC₂₄H₃₀N₈O₄ as (M+H)⁺ 495.1, (M−H)⁻ 493.2. UV: λ=269, 280 nm.

Example 65: Synthesis of(R)-3-(1-acryloylpiperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(79)

In a similar manner as described in Example 62,(R)-3-(1-acryloylpiperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(79) was prepared using acryloyl chloride. MS found for C₂₃H₂₈N₈O₄ as(M+H)⁺ 481.1, (M−H)⁻ 479.2. UV: slope like, no obvious peak.

Example 66: Synthesis of(R,E)-3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(80)

To a solution of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(piperidin-3-ylamino)-1,2,4-triazine-6-carboxamideHCl salt (47 mg, 0.10 mmol) in NMP (4 mL) was added(E)-4-(dimethylamino)but-2-enoic acid (50 mg, 0.30 mmol), DIEA (180 μL,1.0 mmol) and then PyBOP (104 mg, 0.20 mmol). The mixture was stirred atRT for 2 h, quenched with TFA (0.2 mL), diluted with 2 mL water, andsubjected to reverse phase preparative HPLC to isolate the titlecompound (80) as an HCl salt (32 mg). MS found for C₂₆H₃₅N₉O₄ as (M+H)⁺538.2, (M−H)⁻ 536.3. UV: λ=246 nm.

Example 67: Synthesis of(R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(81)

In a similar manner as described in Example 66,(R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(81) was prepared using (E)-4-(cyclopropyl(methyl)amino)but-2-enoicacid. MS found for C₂₈H₃₇N₉O₄ as (M+H)⁺ 564.2, (M−H)⁻ 562.3. UV: λ=247nm.

Example 68: Synthesis of (R)-tert-butyl3-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-ylamino)pyrrolidine-1-carboxylate(82)

In a similar manner as described in Example 60, (R)-tert-butyl3-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-ylamino)pyrrolidine-1-carboxylate(82) was prepared using (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate.MS found for C₂₄H₃₂N₈O₅ as (M+H)⁺ 513.2, (M−H)⁻ 511.3. UV: λ=247, 265,283 nm.

Example 69: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(pyrrolidin-3-ylamino)-1,2,4-triazine-6-carboxamide(83)

(R)-tert-butyl3-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-ylamino)pyrrolidine-1-carboxylate(82) (160 mg) was treated with 4N HCl in dioxane (30 mL) at RT for 3 h.The mixture was concentrated in vacuo to yield the title compound (83)as an HCl salt in quantitative yield. MS found C₁₉H₂₄N₈O₃ as (M+H)⁺413.1, (M−H)⁻ 411.3. UV: λ=264, 283 nm.

Example 70: Synthesis of(R)-3-(1-acryloylpyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(84)

To a solution of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(pyrrolidin-3-ylamino)-1,2,4-triazine-6-carboxamide(83) HCl salt (60 mg, 0.13 mmol) in NMP (4 mL) was added DIEA (160 μL,0.90 mmol) and then acryloyl chloride (25 μL, 0.30 mmol). The mixturewas stirred at RT for 30 min, quenched with TFA (0.2 mL), diluted with 2mL water, and subjected to reverse phase preparative HPLC to afford thetitle compound (84) as an HCl salt. MS found for C₂₂H₂₆N₈O₄ as (M+H)⁺467.1, (M−H)⁻ 465.2. UV: λ=242 nm.

Example 71: Synthesis of(R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(85)

To a solution of (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acid (2.00g, 12.9 mmol) in DCM (60 mL) was added DMF (0.2 mL) and oxalyl chloride(4.42 mL, 51.6 mmol). The mixture was stirred at RT for 4 h andconcentrated in vacuo to dryness to afford(E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. In a similarmanner as described in Example 70,(R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(85) was prepared using (E)-4-(cyclopropyl(methyl)amino)but-2-enoylchloride. MS found for C₂₇H₃₅N₉O₄ as (M+H)⁺ 550.2, (M−H)⁻ 548.3. UV:λ=248 nm.

Example 72: Synthesis of(R)-3-(1-acryloylpyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(86)

In a similar manner as described in Example 70,(R)-3-(1-acryloylpyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(86) was prepared using (R)-tert-butyl3-(methylamino)pyrrolidine-1-carboxylate. MS found for C₂₃H₂₈N₈O₄ as(M+H)⁺ 481.1, (M−H)⁻ 479.2. UV: λ=265 nm.

Example 73: Synthesis of(R)-5-(3-(4-tert-butylbenzamido)piperidin-1-yl)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide(91)

To a solution of 3,5-dichloropyrazine-2-carbonitrile (500 mg, 2.87 mmol)in DMF (10 mL) was added (R)-(3-BOC-amino)piperidine (690 mg, 3.45 mmol)and then DIEA (1.0 mL, 5.74 mmol) in a dropwise manner. The mixture wasstirred at RT for 90 min. The mixture was diluted with EtOAc (200 mL),washed with water ×2, dried, and concentrated in vacuo. The residue wassubjected to flash column chromatography with 0 to 25% EtOAc in DCM toisolate (R)-tert-butyl1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87) (940 mg,97% yield).

A mixture of (R)-tert-butyl1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (400 mg, 1.19mmol), (4-aminophenyl)(morpholino)methanone (490 mg, 2.38 mmol),Pd(OAc)₂ (54 mg, 0.24 mmol), BINAP (150 mg, 0.24 mmol), fine powderCs₂CO₃ (1.55 g, 4.76 mmol) in dioxane (40 mL) was degassed with nitrogenstream for 3 min. The mixture was stirred in a nitrogen atmosphere at115° C. for 2.5 h. The mixture was cooled, diluted with 100 mL EtOAc,filtered through celite, and concentrated in vacuo. The residue wassubjected to flash column chromatography with 0 to 65% EtOAc in DCM togive (R)-tert-butyl1-(5-cyano-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate(88) (yield>85%).

To a solution of (R)-tert-butyl1-(5-cyano-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate(88) in MeOH (15 mL) and DMSO (1.5 mL) was added solid NaOH (200 mg) and30% H₂O₂ (1.5 mL). The mixture was stirred at RT for 20 min, dilutedwith acetonitrile (10 mL), and EtOAc (200 mL) 10 min later. The organicphase was washed with water ×2, dried, and concentrated in vacuo. Theresidue was subjected to flash column chromatography with 0 to 7% MeOHin DCM to isolate (R)-tert-butyl1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate(89) (yield>95%). (R)-tert-butyl1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate(89) was treated with 4N HCl in dioxane (30 mL) for 40 min. The mixturewas concentrated in vacuo to dryness to afford(R)-5-(3-aminopiperidin-1-yl)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamidehydrochloride (90).

To a solution of(R)-5-(3-aminopiperidin-1-yl)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamidehydrochloride (90) (120 mg, 0.27 mmol) in NMP (3 mL) was added DIEA (190μL, 1.08 mmol) and then 4-tert-butylbenzoyl chloride (106 mg, 0.54mmol). The mixture was stirred at RT for 1 h, diluted with 100 mL EtOAc,washed with water ×2, dried, and concentrated in vacuo. The residue wassubjected to flash column chromatography with 0 to 5% MeOH in DCM toisolate the title compound (91) (yield 114 mg). MS found for C₃₂H₃₉N₇O₄as (M+H)⁺ 586.2, (M−H)⁻ 584.3. UV: λ=259, 276, 286, 314, 344, 369 nm.

Example 74: Synthesis of(R)-5-((1-acryloylpiperidin-3-yl)(methyl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide(93)

In a similar manner as described in Example 73,(R)-5-(methyl(piperidin-3-yl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamidehydrochloride (92) was prepared using (R)-tert-butyl3-(methylamino)piperidine-1-carboxylate.

To a solution of(R)-5-(methyl(piperidin-3-yl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamidehydrochloride (92) (40 mg, 0.084 mmol) in NMP (3 mL) was added DIEA (150μL, 0.84 mmol) and then acryloyl chloride (23 mg, 0.25 mmol). Themixture was stirred at RT for 1.5 h, quenched with TFA (0.2 mL), dilutedwith 2 mL water, and subjected to reverse phase preparative HPLC toisolate the title compound (93) as an HCl salt (25 mg). MS found forC₂₅H₃₁N₇O₄ as (M+H)⁺ 494.1, (M−H)⁻ 492.3. UV: λ=275, 280, 313, 343, 369nm.

Example 75: Synthesis of(R,E)-5-((1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)(methyl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide(94)

To a solution of(R)-5-(methyl(piperidin-3-yl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamidehydrochloride (92) (40 mg, 0.084 mmol) in NMP (3 mL) was added(E)-4-(dimethylamino)but-2-enoic acid (42 mg, 0.25 mmol), DIEA (150 μL,0.84 mmol) and then PyBOP (88 mg, 0.17 mmol). The mixture was stirred atRT for 1.5 h, quenched with TFA (0.2 mL), diluted with 2 mL water, andsubjected to reverse phase preparative HPLC to isolate the titlecompound (94) as an HCl salt (29 mg). MS found for C₂₈H₃₈N₈O₄ as (M+H)⁺551.3, (M−H)⁻ 549.3. UV: λ=274, 281, 313, 344, 369 nm.

Example 76: Synthesis of(R)-5-(3-(4-tert-butylbenzamido)piperidin-1-yl)-3-(4-(morpholine-4-carbonyl)phenylamino)picolinamide(99)

To a solution of 3-bromo-5-fluoropicolinonitrile (660 mg, 3.28 mmol) inNMP (20 mL) was added (R)-(3-BOC-amino)piperidine (1.31 g, 6.56 mmol)and then DIEA (2.28 mL, 13.12 mmol) in a dropwise manner. The mixturewas stirred at 100° C. for 90 min. The mixture was diluted with EtOAc(300 mL), washed with water ×2, dried, and concentrated in vacuo. Theresidue was subjected to flash column chromatography with 10 to 50%EtOAc in hexane to isolate (R)-tert-butyl1-(5-bromo-6-cyanopyridin-3-yl)piperidin-3-ylcarbamate (95) (1.30 g,quantitative yield).

A mixture of (R)-tert-butyl1-(5-bromo-6-cyanopyridin-3-yl)piperidin-3-ylcarbamate (95) (300 mg,0.78 mmol), (4-aminophenyl)(morpholino)methanone (322 mg, 1.56 mmol),Pd₂(dba)₃ (73 mg, 0.08 mmol), XantPhos (93 mg, 0.16 mmol), fine powderCs₂CO₃ (765 mg, 2.34 mmol) in dioxane (50 mL) was degassed with nitrogenstream for 3 min. The mixture was stirred in a nitrogen atmosphere at115° C. for 2 h. The mixture was cooled, diluted with 200 mL EtOAc,filtered through celite, and concentrated in vacuo. The residue wassubjected to flash column chromatography with 20 to 100% EtOAc in DCM toisolate (R)-tert-butyl1-(6-cyano-5-(4-(morpholine-4-carbonyl)phenylamino)pyridin-3-yl)piperidin-3-ylcarbamate(96) (yield>80%).

To a solution of (R)-tert-butyl1-(6-cyano-5-(4-(morpholine-4-carbonyl)phenylamino)pyridin-3-yl)piperidin-3-ylcarbamate(96) in MeOH (15 mL) and DMSO (1.5 mL) was added solid NaOH (100 mg) and30% H₂O₂ (1.5 mL). The mixture was stirred at RT for 20 min, dilutedwith acetonitrile (5 mL), and EtOAc (200 mL) 10 min later. The organicphase was washed with water ×2, dried, and concentrated in vacuo. Theresidue was subjected to flash column chromatography with 0 to 5% MeOHin DCM to give (R)-tert-butyl1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)pyridin-3-yl)piperidin-3-ylcarbamate(97) (yield>90%). (R)-tert-butyl1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)pyridin-3-yl)piperidin-3-ylcarbamate(97) was treated with 4N HCl in dioxane (30 mL) for 30 min. The mixturewas concentrated in vacuo to dryness to afford(R)-5-(3-aminopiperidin-1-yl)-3-(4-(morpholine-4-carbonyl)phenylamino)picolinamide,HCl salt (98).

To a solution of(R)-5-(3-aminopiperidin-1-yl)-3-(4-(morpholine-4-carbonyl)phenylamino)picolinamide,HCl salt (98) (99 mg, 0.50 mmol) in DMF (4 mL) was added DIEA (230 μL,1.32 mmol) and then 4-tert-butylbenzoyl chloride (106 mg, 0.54 mmol).The mixture was stirred at RT for 10 min, diluted with 100 mL EtOAc,washed with water ×2, dried, and concentrated in vacuo. The residue wassubjected to flash column chromatography with 0 to 5% MeOH in DCM toisolate the title compound (99). MS found for C₃₃H₄₀N₆O₄ as (M+H)⁺585.2, (M−H)⁻ 583.3. UV: λ=263, 310 nm.

Example 77: Synthesis of(R)-5-(3-(4-tert-butylbenzamido)piperidin-1-yl)-3-(3-methylisothiazol-5-ylamino)picolinamide(100)

In a similar manner as described in Example 76,(R)-5-(3-(4-tert-butylbenzamido)piperidin-1-yl)-3-(3-methylisothiazol-5-ylamino)picolinamide(100) was prepared using 3-methylisothiazol-5-amine. MS found forC₂₆H₃₂N₆O₂S as (M+H)⁺ 493.1, (M−H)⁻ 491.3. UV: λ=307 nm.

Example 78: Synthesis of((R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(3-phenylureido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(101)

To a solution of 6 (50 mg, 0.11 mmol) in NMP (3 mL) were added DIEA (96μL, 0.55 mmol) and then phenyl isocyanate (26 mg, 0.22 mmol), Themixture was stirred at RT for 50 m and treated with TFA (0.2 mL). Themixture was subjected to reverse phase preparative HPLC to isolate thetitle compound (101) (36 mg) as HCl salt. MS found for C₂₇H₃₁N₉O₄ as(M+H)⁺ 546.2, (M−H)⁻ 544.3. UV: λ=240, 257, 276 nm.

Example 79: Synthesis of(R)-3-(3-(3-(4-tert-butylphenyl)ureido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(102)

To a solution of 6 (50 mg, 0.11 mmol) in NMP (3 mL) were added DIEA (96μL, 0.55 mmol) and then 4-tert-butylphenyl isocyanate (39 mg, 0.22mmol), The mixture was stirred at RT for 1 h and treated with TFA (0.2mL). The mixture was subjected to reverse phase preparative HPLC toisolate the title compound (102) (73 mg) as HCl salt. MS found forC₃₁H₃₉N₉O₄ as (M+H)⁺ 602.2, (M−H)⁻ 600.4. UV: λ=243, 260, 278 nm.

Example 80: Synthesis of(R)-3-(3-(3-(4-methoxyphenyl)ureido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(103)

To a solution of 6 (50 mg, 0.11 mmol) in NMP (3 mL) were added DIEA (96μL, 0.55 mmol) and then 4-methoxyphenyl isocyanate (33 mg, 0.22 mmol),The mixture was stirred at RT for 1 h and treated with TFA (0.2 mL). Themixture was subjected to reverse phase preparative HPLC to isolate thetitle compound (103) (75 mg) as HCl salt. MS found for C₂₈H₃₃N₉O₅ as(M+H)⁺ 576.2, (M−H)⁻ 574,2. UV: λ=244, 262, 279 nm.

Example 81: Synthesis of(R)-3-(3-(3,3-dimethylureido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(104)

In a similar manner as described in Example 4,(R)-3-(3-(3,3-dimethylureido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(104) was prepared using dimethylcarbamic chloride. MS found forC₂₃H₃₁N₉O₄ as (M+H)⁺ 498.2, (M−H)⁻ 496.3. UV: λ=273 nm.

Example 82: Synthesis of(R)-3-(3-(4-isopropylpiperidine-1-carboxamido)piperidin-1l-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(105)

Triphosgene (62 mg, 0.21 mmol) was dissolved in 5 mL dry dichloromethaneand stirred in ice bath. To it was added a solution of4-isopropylpiperidine (81 μL, 0.55 mmol) in 5 mL dichloromethane withDIEA (190 μL, 1.1 mmol) in dropwise manner. The mixture was stirred forovernight. It was diluted with 50 mL EtOAc, filtered through a shortsilica plug. The plug was rinsed with EtOAc three times. The filtratewas concentrated in vacuo to dryness.

To a solution of 6 HCl salt (50 mg, 0.11 mmol) in NMP (4 mL) was addedDIEA (191 μL, 1.1 mmol) and then the crude 4-isopropylpiperidinecarbonylchloride as prepared above. The mixture was stirred at RT for 2.5 h,quenched with TFA (0.3 mL) and subjected to reverse phase prep HPLC toisolate the title compound (105) (33 mg) as HCl salt. MS found forC₂₉H₄₁N₉O₄ as (M+H)⁺ 580.3, (M−H)⁻ 578.3. UV: λ=278 nm.

Example 83: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(2-oxo-2-(piperidin-1-yl)acetamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(106)

To a solution of 6 HCl salt (60 mg, 0.13 mmol) in NMP (3 mL) was addedDIEA (180 μL, 1.04 mmol) and then ethyl chloroglyoxylate (43 μL, 0.39mmol). The mixture was stirred at RT for 30 m, diluted with EtOAc,washed with sat ammonium chloride aq solution and water, concentrated invacuo to dryness. It was dissolved in 20 mL THF, To it were added 2 mLwater and lithium hydroxide hydrate (100 mg, 2.38 mmol). The mixture wasstirred for 2 h, acidified, concentrated in vacuo and subjected toreverse phase prep HPLC to isolate(R)-2-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-ylamino)-2-oxoaceticacid as HCl salt. It was dissolved in 3 mL DMF. To it were addedpiperidine (130 μL, 1.30 mmol) and then PyBOP (200 mg, 0.39 mmol). Themixture was stirred at RT for 3.5 h, quenched with TFA (0.3 mL) andsubjected to reverse phase prep HPLC to isolate the title compound (106)(16 mg) as HCl salt. MS found for C₂₇H₃₅N₉O₅ as (M+H)⁺ 566.3, (M−H)⁻564.3. UV: λ=276 nm.

Example 84: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)quinoline-2-carboxamide(107)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)quinoline-2-carboxamide(107) was prepared using quinaldic acid. MS found C₃₀H₃₁N₉O₄ as (M+H)⁺582.2, (M−H)⁻ 580.3. UV: λ=238, 255, 279 nm.

Example 85: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)quinoline-6-carboxamide(108)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)quinoline-6-carboxamide(108) was prepared using quinolin-6-carboxylic acid. MS found C₃₀H₃₁N₉O₄as (M+H)⁺ 582.2, (M−H)⁻ 580.3. UV: λ=237, 255, 275 nm.

Example 86: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(4-(2,2,2-trifluoroethoxy)benzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(109)

In a similar manner as described in Example 10,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(4-(2,2,2-trifluoroethoxy)benzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(109) was prepared using 4-(2,2,2-trifluoroethoxy)benzoic acid. MS foundC₂₉H₃₁F₃N₈O₅ as (M+H)⁺ 629.2, (M−H)⁻ 627.3. UV: λ=270 nm.

Example 87: Synthesis of(R)-3-(3-(5-methylthiophene-2-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(110)

In a similar manner as described in Example 10,(R)-3-(3-(5-methylthiophene-2-carboxamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(110) was prepared using 5-methylthiophene-2-carboxylic acid. MS foundC₂₆H₃₀N₈O₄S as (M+H)⁺ 551.2, (M−H)⁻ 549.2. UV: λ=278 nm.

Example 88: Synthesis of(R)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(111)

In a similar manner as described in Example 10,(R)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(111) was prepared using 4-ethoxybenzoic acid. MS found C₂₉H₃₄N₈O₅ as(M+H)⁺ 575.2, (M−H)⁻ 573.3. UV: λ=262 nm.

Example 89: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(4-propoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(112)

In a similar manner as described in Example 10,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(4-propoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(112) was prepared using 4-propoxybenzoic acid. MS found C₃₀H₃₆N₈O₅ as(M+H)⁺ 589.2, (M−H)⁻ 587.3. UV: λ=263 nm.

Example 90: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(4-isopropoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(113)

In a similar manner as described in Example 10,(R)-3-(3-(4-isopropoxybenzamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(113) was prepared using 4-isopropoxybenzoic acid. MS found C₃₀H₃₆N₈O₅as (M+H)⁺ 589.2, (M−H)⁻ 587.3. UV: λ=263 nm.

Example 91: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-5-methylisoxazole-3-carboxamide(114)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-5-methylisoxazole-3-carboxamide(114) was prepared using 5-methylisoxazole-3-carboxylic acid. MS foundC₂₅H₂₉N₉O₅ as (M+H)⁺ 536.1, (M−H)⁻ 534.3. UV: λ=275 nm.

Example 92: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-5-methylthiazole-2-carboxamide(115)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-5-methylthiazole-2-carboxamide(115) was prepared using 5-methylthiazole-2-carboxylic acid. MS foundC₂₅H₂₉N₉O₄S as (M+H)⁺ 552.1, (M−H)⁻ 550.2. UV: λ=282 nm.

Example 93: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-2-methylthiazole-5-carboxamide(116)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-2-methylthiazole-5-carboxamide(116) was prepared using 2-methylthiazole-5-carboxylic acid. MS foundC₂₅H₂₉N₉O₄S as (M+H)⁺ 552.1, (M−H)⁻ 550.2. UV: λ=265 nm.

Example 94: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)benzo[d]thiazole-2-carboxamide(117)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)benzo[d]thiazole-2-carboxamide(117) was prepared using benzo[d]thiazole-2-carboxylic acid. MS foundC₂₈H₂₉N₉O₄S as (M+H)⁺ 588.1, (M−H)⁻ 586.2. UV: λ=243, 251, 282 nm.

Example 95: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-5-cyclopropylisoxazole-3-carboxamide(118)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-5-cyclopropylisoxazole-3-carboxamide(118) was prepared using 5-cyclopropylisoxazole-3-carboxylic acid. MSfound C₂₇H₃₁N₉O₅ as (M+H)⁺ 562.2, (M−H)⁻ 560.3. UV: λ=273 nm.

Example 96: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(4-phenoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(119)

In a similar manner as described in Example 10,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(4-phenoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(119) was prepared using 4-phenoxybenzoic acid. MS found C₃₃H₃₄N₈O₅ as(M+H)⁺ 623.2, (M−H)⁻ 621.3. UV: λ=265 nm.

Example 97: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)benzo[d]oxazole-2-carboxamide(120)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)benzo[d]oxazole-2-carboxamide(120) was prepared using benzo[d]oxazole-2-carboxylic acid. MS foundC₂₈H₂₉N₉O₅ as (M+H)⁺ 572.1, (M−H)⁻ 570.3. UV: λ=279 nm.

Example 98: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-4-methylthiazole-2-carboxamide(121)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-4-methylthiazole-2-carboxamide(121) was prepared using 4-methylthiazole-2-carboxylic acid. MS foundC₂₅H₂₉N₉O₄S as (M+H)⁺ 552.1, (M−H)⁻ 550.2. UV: λ=281 nm.

Example 99: Synthesis of(R)-3-(3-(3,3-diethylureido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(122)

In a similar manner as described in Example 4,(R)-3-(3-(3,3-diethylureido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(122) was prepared using diethylcarbamic chloride. MS found forC₂₅H₃₅N₉O₄ as (M+H)⁺ 526.2, (M−H)⁻ 524.3. UV: λ=276 nm.

Example 100: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-1-ethyl-1H-benzo[d][1,2,3]triazole-5-carboxamide(123)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-1-ethyl-1H-benzo[d][1,2,3]triazole-5-carboxamide(123) was prepared using 1-ethyl-1H-benzo[d][1,2,3]triazole-5-carboxylicacid. MS found C₂₉H₃₃N₁₁O₄ as (M+H)⁺ 600.2, (M−H)⁻ 598.3. UV: λ=276 nm.

Example 101: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-1-isopropyl-1H-benzo[d][1,2,3]triazole-5-carboxamide(124)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-1-isopropyl-1H-benzo[d][1,2,3]triazole-5-carboxamide(124) was prepared using1-isopropyl-1H-benzo[d][1,2,3]triazole-5-carboxylic acid. MS foundC₃₀H₃₅N₁₁O₄ as (M+H)⁺ 614.2, (M−H)⁻ 612.3. UV: λ=276 nm.

Example 102: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-1-cyclopropyl-1H-benzo[d][1,2,3]triazole-5-carboxamide(125)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-1-cyclopropyl-1H-benzo[d][1,2,3]triazole-5-carboxamide(125) was prepared using1-cyclopropyl-1H-benzo[d][1,2,3]triazole-5-carboxylic acid. MS foundC₃₀H₃₃N₁₁O₄ as (M+H)⁺ 612.2, (M−H)⁻ 610.3. UV: λ=276 nm.

Example 103: Synthesis of(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-1-propyl-H-benzo[d][1,2,3]triazole-5-carboxamide(126)

In a similar manner as described in Example 10,(R)-N-(1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-yl)-1-propyl-1H-benzo[d][1,2,3]triazole-5-carboxamide(126) was prepared using1-propyl-1H-benzo[d][1,2,3]triazole-5-carboxylic acid. MS foundC₃₀H₃₅N₁₁O₄ as (M+H)⁺ 614.2, (M−H)⁻ 612.3. UV: λ=277 nm.

Example 104: Synthesis of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(1-oxoisoindolin-2-yl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(128)

To a solution of 6 HCl salt (70 mg, 0.15 mmol) in NMP (3 mL) was addedDIEA (210 μL, 1.2 mmol) and then methyl 2-bromomethylbenzoate (103 mg,0.45 mmol). The mixture was stirred at RT for 3 h, diluted with EtOAc,washed with brine twice, dried, concentrated in vacuo and subjected toflash column with 0-15% MeOH in dichloromethane to isolate compound 127.It was dissolved in 3 mL NMP. To it was added DIEA (0.2 mL). The mixturewas stirred at 80° C. for 2 h. It was acidified with TFA (0.3 mL) anddirectly subjected to reverse phase prep HPLC to isolate the titlecompound,(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(3-(1-oxoisoindolin-2-yl)piperidin-1-yl)-1,2,4-triazine-6-carboxamid(128) as HCl salt. MS found for C₂₈H₃₀N₈O₄ as (M+H)⁺ 543.2, (M−H)⁻541.3. UV: λ=272 nm.

Example 105: Synthesis of(R)-3-(1-but-2-ynoylpiperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide(129)

In a similar manner as described in Example 66,(R)-3-(1-but-2-ynoylpiperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide(129) was prepared using 4-methylsulfonylaniline and 2-butynoic acid. MSfound for C₂₀H₂₃N₇O₄S as (M+H)⁺ 458.1, (M−H)⁻ 456.1. UV: λ=256, 269, 293nm.

Example 106: Synthesis of(R,E)-3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide(130)

In a similar manner as described in Example 66,(R,E)-3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide(130) was prepared using 4-methylsulfonylaniline and(E)-4-(dimethylamino)but-2-enoic acid. MS found for C₂₂H₃₀N₈O₄S as(M+H)⁺ 503.1, (M−H)⁻ 501.2. UV: λ=258, 272, 286 nm.

Example 107: Synthesis of(R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide(131)

In a similar manner as described in Example 66,(R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide(131) was prepared using 4-methylsulfonylaniline and(E)-4-(cyclopropyl(methyl)amino)but-2-enoic acid. MS found forC₂₄H₃₂N₈O₄S as (M+H)⁺ 529.1, (M−H)⁻ 527.3. UV: λ=259, 270, 287 nm.

Example 108: Synthesis of(R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(quinolin-3-ylamino)-1,2,4-triazine-6-carboxamide(132)

In a similar manner as described in Example 36,(R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(quinolin-3-ylamino)-1,2,4-triazine-6-carboxamide(132) was prepared using 3-aminoquinoline. MS found for C₂₄H₂₉N₉O₂ as(M+H)⁺ 476.1, (M−H)⁻ 474.2. UV: λ=268, 316, 333 nm.

Example 109: Synthesis of(R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(quinolin-7-ylamino)-1,2,4-triazine-6-carboxamide(133)

In a similar manner as described in Example 36,(R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(quinolin-7-ylamino)-1,2,4-triazine-6-carboxamide(133) was prepared using 7-aminoquinoline. MS found for C₂₄H₂₉N₉O₂ as(M+H)⁺ 476.2, (M−H)⁻ 474.3. UV: λ=273, 330, 372 nm.

Example 110: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-methoxyphenylamino)pyrazine-2-carboxamide(137)

(R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate(87) (1.5 g) was treated with 30 mL “4N HCl in dioxane” at RT for 1 h.The mixture was concentrated in vacuo to dryness to afford(R)-5-(3-aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrilehydrochloride (134) in quantitative yield. Compound 134 (1.20 g, 4.4mmol) and p-anisic acid (1.34 g, 8.8 mmol) were dissolved in 20 mL DMFwith DIEA (3.82 mL, 22.0 mmol). To it was added PyBOP (4.58 g, 8.8mmol). The mixture was stirred at RT for 30 m. It was diluted with EtOAc(200 mL), washed with 1N NaOH and water. The organic phase was dried,concentrated and subjected to flash column with 0 to 50% EtOAc in DCM toisolate(R)-N-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-4-methoxybenzamide,compound 135 (yield>90%).

The mixture of compound 135 (70 mg, 0.19 mmol), p-anisidine (70 mg, 0.57mmol), Pd(OAc)₂ (22 mg, 0.10 mmol), BINAP (62 mg, 0.10 mmol), finepowder Cs₂CO₃ (326 mg, 1.00 mmol) in 15 mL dioxane was degassed withnitrogen stream for 3 m. It was stirred at 115° C. under nitrogenatmosphere for 3 h. It was cooled to RT, diluted with 100 mL EtOAc,vigorously stirred, and filtered through celite. The filtrate wasconcentrated in vacuo and subjected to flash column with 0 to 3% MeOH indichloromethane to afford(R)-N-(1-(5-cyano-6-(4-methoxyphenylamino)pyrazin-2-yl)piperidin-3-yl)-4-methoxybenzamide,compound 136.

Compound 136 was dissolved in the mixture of 3 mL DMSO and 6 mL MeOH andstirred at RT. To it were added one crystal chip of NaOH (about 50 to100 mg) and the 1 mL 30% H₂O₂. The mixture was stirred at RT for 2.5 h,diluted with 3 mL acetonitrile, and concentrated in vacuo. The mixturewas diluted with water, acidified with HCl till pH about 2. The solidwas isolated by filtration, washed with water and MTBE. It was dried invacuum to afford(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-methoxyphenylamino)pyrazine-2-carboxamide(137) as HCl salt (25 mg). MS found C₂₅H₂₈N₆O₄ as (M+H)⁺ 477.1, (M−H)⁻475.3. UV: λ=258, 279, 303, 338, 373 nm.

Example 111: Synthesis of(R)-3-(4-ethoxyphenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(138)

In a similar manner as described in Example 110,(R)-3-(4-ethoxyphenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(138) was prepared using 4-ethoxyaniline. MS found for C₂₆H₃₀N₆O₄ as(M+H)⁺ 491.1, (M−H)⁻ 489.2. UV: λ=258, 279, 303, 339, 373 nm.

Example 112: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(2-methoxyethoxy)phenylamino)pyrazine-2-carboxamide(139)

In a similar manner as described in Example 110,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(2-methoxyethoxy)phenylamino)pyrazine-2-carboxamide(139) was prepared using 4-(2-methoxyethoxy)aniline. MS found forC₂₇H₃₂N₆O₅ as (M+H)⁺ 521.2, (M−H)⁻ 519.3. UV: λ=257, 279, 303, 338, 373nm.

Example 113: Synthesis of(R)-3-(4-(2-ethoxyethoxy)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(140)

In a similar manner as described in Example 110,(R)-3-(4-(2-ethoxyethoxy)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(140) was prepared using 4-(2-ethoxyethoxy)aniline. MS found forC₂₈H₃₄N₆O₅ as (M+H)⁺ 535.2, (M−H)⁻ 533.3. UV: λ=257, 279, 303, 338, 373nm.

Example 114: Synthesis of(R)-3-(6-ethoxypyridin-3-ylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(141)

The mixture of compound 135 (65 mg, 0.17 mmol), 6-ethoxypyridin-3-amine(71 mg, 0.51 mmol), Pd(OAc)₂ (19 mg, 0.085 mmol), BINAP (53 mg, 0.085mmol), fine powder Cs₂CO₃ (280 mg, 0.85 mmol) in 10 mL dioxane wasdegassed with nitrogen stream for 3 m. It was stirred at 115° C. undernitrogen atmosphere for 3 h. It was cooled to RT, diluted with 100 mLEtOAc, vigorously stirred, and filtered through celite. The filtrate wasconcentrated in vacuo and subjected to flash column with 0 to 4% MeOH indichloromethane to afford(R)-N-(1-(5-cyano-6-(6-ethoxypyridin-3-ylamino)pyrazin-2-yl)piperidin-3-yl)-4-methoxybenzamide.It was dissolved in the mixture of 3 mL DMSO and 6 mL MeOH and stirredat RT. To it were added one crystal chip of NaOH (about 50 to 100 mg)and the 1 mL 30% H₂O₂. The mixture was stirred at RT for 1 h, dilutedwith 3 mL acetonitrile, and concentrated in vacuo. The mixture wasacidified with TFA (1 mL) and directly subjected to reverse phase prepHPLC to isolate(R)-3-(6-ethoxypyridin-3-ylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(141) as HCl salt (58 mg). MS found C₂₅H₂₉N₇O₄ as (M+H)⁺ 492.2, (M−H)⁻490.3. UV: λ=257, 278, 300, 336, 369 nm.

Example 115: Synthesis of(R)-3-(4-(2-(dimethylamino)ethoxy)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(142)

In a similar manner as described in Example 114,(R)-3-(4-(2-(dimethylamino)ethoxy)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(142) was prepared using 4-(2-(dimethylamino)ethoxy)aniline. MS foundfor C₂₈H₃₅N₇O₄ as (M+H)⁺ 534.2, (M−H)⁻ 532.3. UV: λ=258, 279, 303, 337,373 nm.

Example 116: Synthesis of(R)-2-(4-(3-carbamoyl-6-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazin-2-ylamino)phenoxy)-N,N-dimethylethanamineoxide (143)

(R)-2-(4-(3-carbamoyl-6-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazin-2-ylamino)phenoxy)-N,N-dimethylethanamineoxide (143) was isolated as a byproduct during the synthesis of(R)-3-(4-(2-(dimethylamino)ethoxy)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(142) in Example 115. MS found for C₂₈H₃₅N₇O₅ as (M+H)⁺ 550.2, (M−H)⁻548.4. UV: λ=258, 279, 303, 337, 373 nm.

Example 117: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(methylsulfonyl)phenylamino)pyrazine-2-carboxamide(144)

In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(methylsulfonyl)phenylamino)pyrazine-2-carboxamide(144) was prepared using 4-methylsulfonylaniline. MS found forC₂₅H₂₈N₆O₅S as (M+H)⁺ 525.1, (M−H)⁻ 523.3. UV: λ=256, 262, 274, 293,318, 346, 367 nm.

Example 118: Synthesis of(R)-3-(4-(dimethylcarbamoyl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(145)

In a similar manner as described in Example 114,(R)-3-(4-(dimethylcarbamoyl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(145) was prepared using 4-amino-N,N-dimethylbenzamide. MS found forC₂₇H₃₁N₇O₄ as (M+H)⁺ 518.2, (M−H)⁻ 516.3. UV: λ=256, 262, 272, 288, 313,342, 370 nm.

Example 119: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carboxamide(146)

In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carboxamide(146) was prepared using 3-methylisothiazol-5-amine. MS found forC₂₂H₂₅N₇O₃S as (M+H)⁺ 468.1, (M−H)⁻ 466.2. UV: λ=257, 262, 271, 289,314, 341, 368 nm.

Example 120: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(quinolin-6-ylamino)pyrazine-2-carboxamide(147)

In a similar manner as described in Example 110,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(quinolin-6-ylamino)pyrazine-2-carboxamide(147) was prepared using 6-aminoquinoline. MS found for C₂₇H₂₇N₇O₃ as(M+H)⁺ 498.2, (M−H)⁻ 496.3. UV: λ=264, 273, 284, 300, 338, 369 nm.

Example 121: Synthesis of(R)-3-(benzo[d]thiazol-6-ylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(148)

In a similar manner as described in Example 110,(R)-3-(benzo[d]thiazol-6-ylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(148) was prepared using 6-aminobenzothiazole. MS found for C₂₅H₂₅N₇O₃Sas (M+H)⁺ 504.1, (M−H)⁻ 502.3. UV: λ=317, 348, 370 nm.

Example 122: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazine-2-carboxamide(149)

In a similar manner as described in Example 110,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazine-2-carboxamide(149) was prepared using 4-(tetrahydro-2H-pyran-4-yl)aniline. MS foundfor C₂₉H₃₄N₆O₄ as (M+H)⁺ 531.2, (M−H)⁻ 529.3. UV: λ=257, 279, 304, 335,372 nm.

Example 123: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-morpholinophenylamino)pyrazine-2-carboxamide(150)

In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-morpholinophenylamino)pyrazine-2-carboxamide(150) was prepared using 4-morpholinoaniline. MS found for C₂₈H₃₃N₇O₄ as(M+H)⁺ 532.2, (M−H)⁻ 530.3. UV: λ=259, 285, 309, 345, 372 nm.

Example 124: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(6-morpholinopyridin-3-ylamino)pyrazine-2-carboxamide(151)

In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(6-morpholinopyridin-3-ylamino)pyrazine-2-carboxamide(151) was prepared using 6-morpholinopyridin-3-amine. MS found forC₂₇H₃₂N₈O₄ as (M+H)⁺ 533.2, (M−H)⁻ 531.3. UV: λ=257, 285, 308, 337, 367nm.

Example 125: Synthesis of(R)-3-(3-fluoro-4-morpholinophenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(152)

In a similar manner as described in Example 114,(R)-3-(3-fluoro-4-morpholinophenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(152) was prepared using 3-fluoro-4-morpholinoaniline. MS found forC₂₈H₃₂FN₇O₄ as (M+H)⁺ 550.2, (M−H)⁻ 548.3. UV: λ=310, 343, 372 nm.

Example 126: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(3-oxomorpholino)phenylamino)pyrazine-2-carboxamide(153)

In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(3-oxomorpholino)phenylamino)pyrazine-2-carboxamide(153) was prepared using 4-(4-aminophenyl)morpholin-3-one. MS found forC₂₈H₃₁N₇O₅ as (M+H)⁺ 546.2, (M−H)⁻ 544.3. UV: λ=261, 285, 308, 338, 372nm.

Example 127: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(2-oxopyridin-1(2H)-yl)phenylamino)pyrazine-2-carboxamide(154)

In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(2-oxopyridin-1(2H)-yl)phenylamino)pyrazine-2-carboxamide (154) was prepared using1-(4-aminophenyl)pyridin-2(1H)-one. MS found for C₂₉H₂₉N₇O₄ as (M+H)⁺540.1, (M−H)⁻ 538.3. UV: λ=260, 285, 308, 346, 369 nm. Synthesis of1-(4-aminophenyl)pyridin-2(1H)-one: The mixture of 4-iodoaniline (1.00g, 4.56 mmol), 2-hydroxypyridine (650 mg, 6.84 mmol), fine powder Cs₂CO₃(2.97 g, 9.12 mmol), fine powder CuI (180 mg, 0.92 mmol),8-hydroxyquinoline (140 mg, 0.92 mmol) in 6 mL DMSO and 10 mL dioxanewas stirred in a sealed tube at 120° C. for 15 h. The mixture wasdiluted with 300 mL EtOAc, filtered through celite, washed with brine,dried, concentrated and subjected to flash column with 0 to 7% MeOH indichloromethane to isolate this compound (590 mg, yield 70%).

Example 128: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(2-oxopiperidin-1-yl)phenylamino)pyrazine-2-carboxamide(155)

Compound(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(2-oxopyridin-1(2H)-yl)phenylamino)pyrazine-2-carboxamide(154) (20 mg) was dissolved in 20 mL MeOH. To it was added 10% Pd/C (20mg). The mixture was stirred at RT for overnight under a hydrogenballoon. It was filtered through celite, concentrated in vacuo andsubjected to reverse preparative HPLC to isolate(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(2-oxopiperidin-1-yl)phenylamino)pyrazine-2-carboxamide(155) as HCl salt. MS found for C₂₉H₃₃N₇O₄ as (M+H)⁺ 544.2, (M−H)⁻542.3. UV: λ=259, 282, 307, 337, 372 nm.

Example 129: Synthesis of(R)-5-(3-(4-tert-butylbenzamido)piperidin-1-yl)-3-(4-(4-methylpiperazin-1-yl)phenylamino)pyrazine-2-carboxamide(156)

In a similar manner as described in Example 114,(R)-5-(3-(4-tert-butylbenzamido)piperidin-1-yl)-3-(4-(4-methylpiperazin-1-yl)phenylamino)pyrazine-2-carboxamide(156) was prepared using 4-(4-methylpiperazin-1-yl)aniline and4-tert-butylbenzoyl chloride. MS found for C₃₂H₄₂N₈O₂ as (M+H)⁺ 571.3,(M−H)⁻ 569.4. UV: λ=309, 346, 372 nm.

Example 130: Synthesis of(R)-5-(3-(4-tert-butylbenzamido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(157)

In a similar manner as described in Example 114,(R)-5-(3-(4-tert-butylbenzamido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(157) was prepared using 4-(1-methylpiperidin-4-yl)aniline and4-tert-butylbenzoyl chloride. MS found for C₃₃H₄₃N₇O₂ as (M+H)⁺ 570.3,(M−H)⁻ 568.4. UV: λ=264, 277, 305, 335, 372 nm.

Example 131: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(158)

In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(158) was prepared using 4-(1-methylpiperidin-4-yl)aniline. MS found forC₃₀H₃₇N₇O₃ as (M+H)⁺ 544.2, (M−H)⁻ 542.3. UV: λ=258, 280, 305, 336, 372nm.

Example 132: Synthesis of(R)-3-(4-(1-ethylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(159)

In a similar manner as described in Example 114,(R)-3-(4-(1-ethylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(159) was prepared using 4-(1-ethylpiperidin-4-yl)aniline. MS found forC₃₁H₃₉N₇O₃ as (M+H)⁺ 558.2, (M−H)⁻ 556.3. UV: λ=258, 280, 305, 336, 372nm.

Example 133: Synthesis of(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(160)

In a similar manner as described in Example 114,(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(160) was prepared using 4-(1-cyclopropylpiperidin-4-yl)aniline. MSfound for C₃₂H₃₉N₇O₃ as (M+H)⁺ 570.2, (M−H)⁻ 568.3. UV: λ=258, 280, 305,336, 372 nm.

Example 134: Synthesis of(R)-3-(4-(1-isopropylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(164)

The mixture of compound 135 (580 mg, 1.56 mmol), tert-butyl4-(4-aminophenyl)piperidine-1-carboxylate (870 mg, 3.12 mmol), Pd(OAc)₂(70 mg, 0.31 mmol), BINAP (200 mg, 0.31 mmol), fine powder Cs₂CO₃ (2.04g, 6.24 mmol) in 80 mL dioxane was degassed with nitrogen stream for 3m. It was stirred at 115° C. under nitrogen atmosphere for 3 h. It wascooled to RT, diluted with 300 mL EtOAc, vigorously stirred, andfiltered through celite. The filtrate was concentrated in vacuo andsubjected to flash column with 0 to 5% MeOH in dichloromethane to affordcompound 161.

Compound 161 was dissolved in the mixture of 10 mL DMSO and 40 mL MeOHand stirred at RT. To it were added three crystal chip of NaOH (about150 to 300 mg) and the 10 mL 30% H₂O₂. The mixture was stirred at RT for1 h, diluted with 10 mL acetonitrile. To the mixture then was poured 200mL water. The mixture was vigorously stirred. The solid precipitateswere isolated by filtration, washed with water thoroughly and dried invacuo to afford compound 162 in good purity (1.00 g).

Compound 162 was treated with 50 mL “4N HCl in dioxane” at RT forovernight. The mixture was concentrated in vacuo and pumped to drynessto afford(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(163) as HCl salt.

Compound 163 (70 mg, 0.12 mmol) was dissolved in 8 mL 1,2-dichloroethaneand 8 mL dioxane with DIEA (105 μL, 0.60 mmol). To it was added acetone(180 μL, 2.4 mmol). The mixture was stirred at RT for 2 h. To it wereadded acetic acid (68 μL, 1.2 mmol) and then NaBH(OAc)₃ (127 mg, 0.60mmol). The mixture was stirred for overnight. It was diluted with 2 mLwater, concentrated in vacuo, treated with TFA (0.2 mL) and subjected toreverse phase preparative HPLC to isolate(R)-3-(4-(1-isopropylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(164) as HCl salt (34 mg). MS found for C₃₂H₄₁N₇O₃ as (M+H)⁺ 572.3,(M−H)⁻ 570.4. UV: λ=258, 279, 305, 335, 372 nm.

Example 135: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(165)

In a similar manner as described in Example 134,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(165) was prepared using cyclopentanone. MS found for C₃₄H₄₃N₇O₃ as(M+H)⁺ 598.3, (M−H)⁻ 596.4. UV: λ=258, 279, 305, 335, 372 nm.

Example 136: Synthesis of(R)-3-(4-(1-(cyanomethyl)piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(166)

Compound 163 (50 mg, 0.085 mmol) was dissolved in 3 mL NMP. To it wereadded DIEA (74 μL, 0.43 mmol) and then bromoacetonitrile (31 mg, 0.26mmol). The mixture was stirred at RT for 4 h. It was acidified with TFA(0.2 mL) and directly subjected to reverse phase preparative HPLC toisolate(R)-3-(4-(1-(cyanomethyl)piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(166) as HCl salt (37 mg). MS found for C₃₁H₃₆N₈O₃ as (M+H)⁺ 569.2,(M−H)⁻ 567.3. UV: λ=256, 280, 305, 335, 372 nm.

Example 137: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(167)

Compound 163 (50 mg, 0.085 mmol) was dissolved in 3 mL NMP. To it wereadded DIEA (74 μL, 0.43 mmol) and then 2,2,2-trifluoroethyltrifluoromethanesulfonate (60 mg, 0.26 mmol). The mixture was stirred atRT for 4 h. It was acidified with TFA (0.2 mL) and directly subjected toreverse phase preparative HPLC to isolate(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(167) as HCl salt (8 mg). MS found for C₃₁H₃₆F₃N₇O₃ as (M+H)⁺ 612.2,(M−H)⁻ 610.3. UV: λ=305, 335, 372 nm.

Example 138: Synthesis of(R)-3-(4-(1-formylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(168)

Compound 163 (36 mg, 0.06 mmol) was dissolved in 3 mL DMF with 0.5 mLDIEA in a sealed tube. The mixture was stirred at 130° C. for 2 days. Itwas cooled to RT, acidified with 1 mL TFA, and directly subjected toreverse phase preparative HPLC to isolate(R)-3-(4-(1-formylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(168) as HCl salt (9 mg). MS found for C₃₀H₃₅N₇O₄ as (M+H)⁺ 558.2,(M−H)⁻ 556.3. UV: λ=257, 279, 304, 335, 372 nm.

Example 139: Synthesis of(R)-3-(4-(1-acetylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(169)

Compound 163 (42 mg, 0.07 mmol) was dissolved in 2 mL DMSO with 1 mLacetic acid and 1 mL Et₃N. To the mixture was added PyBOP (200 mg, 0.38mmol). The mixture was stirred for overnight, concentrated in vacuo,acidified with TFA (1 mL), and directly subjected to reverse phasepreparative HPLC to isolate(R)-3-(4-(1-acetylpiperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(169) as HCl salt (12 mg). MS found for C₃₁H₃₇N₇O₄ as (M+H)⁺ 572.2,(M−H)⁻ 570.4. UV: λ=257, 279, 304, 335, 372 nm.

Example 140: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(1-propionylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(170)

Compound 163 (50 mg, 0.085 mmol) was dissolved in 3 mL NMP. To it wereadded DIEA (74 μL, 0.425 mmol) and then propionyl chloride (23 mg, 0.255mmol). The reaction was quenched in 10 m using TFA (0.2 mL). The mixturewas directly subjected to reverse phase preparative HPLC to isolate(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(1-propionylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(170) as HCl salt. MS found for C₃₂H₃₉N₇O₄ as (M+H)⁺ 586.2, (M−H)⁻584.4. UV: λ=257, 279, 304, 335, 372 nm.

Example 141: Synthesis of(R)-3-(4-(1-(2-cyanoacetyl)piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(171)

Compound 163 (50 mg, 0.085 mmol) was dissolved in 3 mL NMP. To it wereadded cyanoacetic acid (22 mg, 0.255 mmol), DIEA 150 μL, 0.85 mmol) andthen PyBOP (88 mg, 0.17 mmol). The reaction was quenched in 1.5 h usingTFA (0.2 mL). The mixture was directly subjected to reverse phasepreparative HPLC to isolate(R)-3-(4-(1-(2-cyanoacetyl)piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(171) as HCl salt. MS found for C₃₂H₃₆N₈O₄ as (M+H)⁺ 597.2, (M−H)⁻595.3. UV: λ=305, 336, 372 nm.

Example 142: Synthesis of(R)-3-(4-(1-(dimethylcarbamoyl)piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(172)

Compound 163 (40 mg, 0.07 mmol) was dissolved in 3 mL NMP. To it wereadded DIEA (125 μL, 0.71 mmol) and then dimethylcarbamic chloride (20μL, 0.21 mmol). The reaction was quenched in 1 h using TFA (0.2 mL). Themixture was directly subjected to reverse phase preparative HPLC toisolate(R)-3-(4-(1-(dimethylcarbamoyl)piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(172) as HCl salt (13 mg). MS found for C₃₂H₄₀N₈O₄ as (M+H)⁺ 601.3,(M−H)⁻ 599.3. UV: λ=257, 279, 304, 336, 372 nm.

Example 143: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(1-(methylsulfonyl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(173)

Compound 163 (32 mg, 0.056 mmol) was dissolved in 3 mL NMP. To it wereadded DIEA (60 μL, 0.34 mmol) and then methanesulfonyl chloride (13 μL,0.17 mmol). The reaction was quenched in 20 m using TFA (0.1 mL). Themixture was directly subjected to reverse phase preparative HPLC toisolate(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(1-(methylsulfonyl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(173) as HCl salt. MS found for C₃₀H₃₇N₇O₅S as (M+H)⁺ 608.2, (M−H)⁻606.3. UV: λ=304, 335, 372 nm.

Example 144: Synthesis of(R)-3-(4-(4-(dimethylcarbamoyl)piperidin-1-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(177)

In a similar manner as described in Example 110, (R)-ethyl1-(4-(3-cyano-6-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)piperidine-4-carboxylate(174) was prepared using ethyl1-(4-aminophenyl)piperidine-4-carboxylate. Compound 174 (155 mg, 0.27mmol) was dissolved in 20 mL THF. To it was added lithium hydroxidehydrate (61 mg, 1.5 mmol) and 5 mL water. The mixture was stirred at RTfor overnight and concentrated in vacuo to dryness to afford crudecompound 175. It was dissolved in 15 mL MeOH and 3 mL DMSO. To it wasadded NaOH (100 mg) and then 2 mL 30% H₂O₂. The mixture was stirred atRT for 1 h and diluted with acetonitrile (3 mL). The mixture wasconcentrated in vacuo, acidified and subjected to reverse phasepreparative HPLC to isolate compound 176 as HCl salt.

Compound 176 (70 mg, 0.12 mmol) was dissolved in 3 mL NMP. To it wereadded dimethylamine (2.0M solution in THF, 0.6 mL, 1.2 mmol) and thenPyBOP (125 mg, 0.24 mmol). The mixture was stirred for overnight. It wasquenched with TFA (1 mL) and then directly subjected to reverse phasepreparative HPLC to isolate(R)-3-(4-(4-(dimethylcarbamoyl)piperidin-1-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(177) as HCl salt (36 mg). MS found for C₃₂H₄₀N₈O₄ as (M+H)⁺ 601.2,(M−H)⁻ 599.4. UV: λ=262, 285, 308, 335, 369 nm.

Example 145: Synthesis of(R)-3-(4-(methylsulfonyl)phenylamino)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(180)

Compound 134 (600 mg, 2.2 mmol) was dissolved in 10 mL DMF and 10 mLdioxane. To the stirred solution were added DIEA (1.9 mL, 11 mmol) andthen dropwise 1-piperidinecarbonyl chloride (550 μL, 4.4 mmol). Themixture was stirred for overnight, concentrated in vacuo, taken into 200mL EtOAc, washed with brine, dried, concentrated and subjected to flashcolumn with 0 to 4% MeOH in dichloromethane to afford compound 178 (730mg, 95%). The mixture of compound 178 (90 mg, 0.26 mmol),4-methylsulfonylaniline (133 mg, 0.78 mmol), Pd(OAc)₂ (30 mg, 0.13mmol), BINAP (81 mg, 0.13 mmol), fine powder Cs₂CO₃ (430 mg, 1.30 mmol)in 15 mL dioxane was degassed with nitrogen stream for 3 m. It wasstirred at 115° C. under nitrogen atmosphere for 3 h. It was cooled toRT, diluted with 100 mL EtOAc, vigorously stirred, and filtered throughcelite. The filtrate was concentrated in vacuo and subjected to flashcolumn with 0 to 5% MeOH in dichloromethane to afford compound 179.Compound 179 was dissolved in the mixture of 3 mL DMSO and 6 mL MeOH andstirred at RT. To it were added one crystal chip of NaOH (about 50 to100 mg) and the 1 mL 30% H₂O₂. The mixture was stirred at RT for 1 h,diluted with 3 mL acetonitrile, and concentrated in vacuo. It wasacidified with TFAS (0.2 mL) and directly subjected to reverse phasepreparative HPLC to afford(R)-3-(4-(methylsulfonyl)phenylamino)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(180) as HCl salt (61 mg). MS found C₂₃H₃₁N₇O₄S as (M+H)⁺ 502.1, (M−H)⁻500.2. UV: λ=280, 293, 319, 346, 367 nm.

Example 146: Synthesis of(R)-3-(4-(4-methylpiperazin-1-yl)phenylamino)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(181)

In a similar manner as described in Example 145,(R)-3-(4-(4-methylpiperazin-1-yl)phenylamino)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(181) was prepared using 4-(4-methylpiperazin-1-yl)aniline. MS found forC₂₇H₃₉N₉O₂ as (M+H)⁺ 522.3, (M−H)⁻ 520.4. UV: λ=310, 346, 373 nm.

Example 147: Synthesis of(R)-3-(4-(1-methylpiperidin-4-yl)phenylamino)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(182)

In a similar manner as described in Example 145,(R)-3-(4-(1-methylpiperidin-4-yl)phenylamino)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(182) was prepared using 4-(1-methylpiperidin-4-yl)aniline. MS found forC₂₈H₄N₈O₂ as (M+H)⁺ 521.3, (M−H)⁻ 519.4. UV: λ=268, 278, 306, 336, 372nm.

Example 148: Synthesis of(R)-3-(4-(1-formylpiperidin-4-yl)phenylamino)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(183)

In a similar manner as described in Example 138 and Example 145,(R)-3-(4-(1-formylpiperidin-4-yl)phenylamino)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(183) was prepared. MS found for C₂₈H₃₈N₈O₃ as (M+H)⁺ 535.2, (M−H)⁻533.3. UV: λ=268, 277, 306, 336, 373 nm.

Example 149: Synthesis of(R)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)-3-(4-(1-propionylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(184)

In a similar manner as described in Example 140 and Example 145,(R)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)-3-(4-(1-propionylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(184) was prepared. MS found for C₃₀H₄₂N₈O₃ as (M+H)⁺ 563.2, (M−H)⁻561.4. UV: λ=268, 277, 305, 336, 372 nm.

Example 150: Synthesis of(R)-3-(4-(1-(2-cyanoacetyl)piperidin-4-yl)phenylamino)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(185)

In a similar manner as described in Example 141 and Example 145,(R)-3-(4-(1-(2-cyanoacetyl)piperidin-4-yl)phenylamino)-5-(3-(piperidine-1-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(185) was prepared. MS found for C₃₀H₃₉N₉O₃ as (M+H)⁺ 574.2, (M−H)⁻572.4. UV: λ=268, 277, 306, 336, 372 nm.

Example 151: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(methylsulfonyl)phenylamino)pyrazine-2-carboxamide(186)

In a similar manner as described in Example 145,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(methylsulfonyl)phenylamino)pyrazine-2-carboxamide(186) was prepared using dimethylcarbamic chloride. MS found forC₂₀H₂₇N₇O₄S as (M+H)⁺ 462.1, (M−H)⁻ 460.2. UV: λ=280, 293, 319, 346, 367nm.

Example 152: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-propionylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(187)

In a similar manner as described in Example 149,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-propionylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(187) was prepared using dimethylcarbamic chloride. MS found forC₂₇H₃₈N₈O₃ as (M+H)⁺ 523.2, (M−H)⁻ 521.4. UV: λ=268, 276, 305, 336, 372nm.

Example 153: Synthesis of(R)-3-(4-(1-(2-cyanoacetyl)piperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(188)

In a similar manner as described in Example 149,(R)-3-(4-(1-(2-cyanoacetyl)piperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(188) was prepared using dimethylcarbamic chloride. MS found forC₂₇H₃₅N₉O₃ as (M+H)⁺ 534.2, (M−H)⁻ 532.3. UV: λ=268, 277, 305, 336, 372nm.

Example 154: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(189)

In a similar manner as described in Example 134,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(189) was prepared using dimethylcarbamic chloride. MS found forC₂₄H₃₄N₈O₂ as (M+H)⁺ 467.2, (M−H)⁻ (weak). UV: λ=268, 277, 306, 336, 373nm.

Example 155: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(190)

In a similar manner as described in Example 135,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(190) was prepared using dimethylcarbamic chloride. MS found forC₂₉H₄₂N₈O₂ as (M+H)⁺ 535.3, (M−H)⁻533.4. UV: λ=268, 277, 306, 336, 373nm. Proton NMR (CD₃OD): δ 7.65 (1H, s), 7.61 (2H, d, J=8.5 Hz), 7.21(2H, d, J=8.5 Hz), 4.2 (1H, dd, J=13.0; 3.5 Hz), 4.20 (1H, m), 3.77 (1H,m), 3.71 (2H, d, J=12.5 Hz), 3.56 (1H, m), 3.27-3.10 (4H, m), 2.87 (7H,s), 2.25-2.10 (4H, m), 2.05-1.85 (7H, m), 1.80-1/0.65 (5H, m) ppm.

Example 156: Synthesis of(R,E)-5-((1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-yl)(methyl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide(191)

In a similar manner as described in Example 75,(R,E)-5-((1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-yl)(methyl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide(191) was prepared using (E)-4-(cyclopropyl(methyl)amino)but-2-enoicacid. MS found for C₃₀H₄₀N₈O₄ as (M+H)⁺ 577.2, (M−H)⁻ 575.4. UV: λ=274,281, 313, 344, 369 nm.

Example 157: Synthesis of(R)-5-((1-but-2-ynoylpiperidin-3-yl)(methyl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide(192)

In a similar manner as described in Example 75,(R)-5-((1-but-2-ynoylpiperidin-3-yl)(methyl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide(192) was prepared using 2-butynoic acid. MS found for C₂₆H₃₁N₇O₄ as(M+H)⁺ 506.2, (M−H)⁻ 504.3. UV: λ=313, 342, 369 nm.

Example 158: Synthesis of(R,E)-5-((1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)(methyl)amino)-3-(4-phenoxyphenylamino)pyrazine-2-carboxamide(193)

In a similar manner as described in Example 75,(R,E)-5-((1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)(methyl)amino)-3-(4-phenoxyphenylamino)pyrazine-2-carboxamide(193) was prepared using 4-phenoxyaniline. MS found for C₂₉H₃₅N₇O₃ as(M+H)⁺ 530.2, (M−H)⁻ 528.3. UV: λ=265, 274, 302, 335, 372 nm.

Example 159: Synthesis of(R)-5-(4-cyanophenylamino)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(194)

In a similar manner as described in Example 110,(R)-5-(4-cyanophenylamino)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(194) was prepared using 4-aminobenzonitrile and 4-ethoxybenzoic acid.MS found for C₂₅H₂₆N₈O₃ as (M+H)⁺ 487.1, (M−H)⁻ 485.3. UV: λ=275 nm.

Example 160: Synthesis of(R)-3-(4-isopropylphenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(195)

In a similar manner as described in Example 110,(R)-3-(4-isopropylphenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(195) was prepared using 4-isopropylaniline. MS found for C₂₇H₃₂N₆O₃ as(M+H)⁺ 489.1, (M−H)⁻ 487.3. UV: λ=257, 279, 304, 335, 372 nm.

Example 161: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(1,1-dioxothiomorpholino)phenylamino)pyrazine-2-carboxamide(196)

In a similar manner as described in Example 110,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-dioxothiomorpholinophenylamino)pyrazine-2-carboxamide(196) was prepared using 4-(1,1-dioxothiomorpholino)aniline. MS foundfor C₂₈H₃₃N₇O₅S as (M+H)⁺ 580.1, (M−H)⁻ 578.2. UV: λ=309, 349, 375 nm.

Example 162: Synthesis of(R)-3-(2-fluoro-4-(piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(201)

tert-Butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(197, 1.95 g, 6.32 mmol), 4-bromo-2fluoroaniline (1.00 g, 5.26 mmol),Pd(dppf)Cl₂.DCM (0.43 g, 0.526 mmol), K₂CO₃ (1.45 g, 10.5 mmol) weremixed in 40 mL dioxane and 20 mL water. The mixture was degassed with N₂stream for 3 min and stirred at 90° C. in N₂ atmosphere for overnight.The mixture was cooled to RT, concentrated in vacuo, diluted with 120 mLEtOAc, washed with water ×2, dried, concentrated, and subjected tosilica flash column to isolate tert-butyl4-(4-amino-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (198,1.55 g, quantitative yield) using 0 to 25% EtOAc in hexane. It wasdissolved in 150 mL iPrOH, and to it was hydrogenated with 10% Pd/Cusing a balloon for overnight. The mixture was filtered through celite,concentrated in vacuo to afford tert-butyl4-(4-amino-3-fluorophenyl)piperidine-1-carboxylate (199) in quantitativeyield.

In a similar manner as described in Example 110, (R)-tert-butyl4-(4-(3-carbamoyl-6-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazin-2-ylamino)-3-fluorophenyl)piperidine-1-carboxylate(200) was prepared using tert-butyl4-(4-amino-3-fluorophenyl)piperidine-1-carboxylate. It was treated with1:1 TFA/DCM at RT for 30 min, and(R)-3-(2-fluoro-4-(piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(201) was isolated as HCl salt using reverse phase prep HPLC using 5 mMHCl (aq) and neat MeCN as mobile phases. MS found for C₂₉H₃₄FN₇O₃ as(M+H)⁺ 548.2, (M−H)⁻ 546.3. UV: λ=257, 280, 306, 334, 369 nm. Proton NMR(CD₃OD): δ 8.34 (1H, m), 7.79 (2H, d, J=9.0 Hz), 7.72 (1H, s), 7.03 (1H,d, J=12.5 Hz), 6.99 (2H, d, J=8.5 Hz), 6.96 (1H, d, J=9.5 Hz), 4.46 (1H,m), 4.18 (1H, m), 4.12 (1H, m), 3.86 (3H, m), 3.45 (1H, s), 3.42 (1H,s), 3.25 (2H, m), 3.08 (2H, m), 2.80 (1H, m), 2.11 (1H, m), 2.01-1.94(3H, m), 1.81-1.70 (4H, m) ppm.

Example 163: Synthesis of(R)-3-(3-fluoro-4-(piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(202)

In a similar manner as described in Example 162,(R)-3-(3-fluoro-4-(piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide(202) was prepared using 4-bromo-3-fluoroaniline. MS found forC₂₉H₃₄FN₇O₃ as (M+H)⁺ 548.2, (M−H)⁻ 546.3. UV: λ=259, 281, 307, 335, 372nm. NMR (CD₃OD): δ 7.78 (2H, d, J=9.0 Hz), 7.71 (1H, s), 7.61 (1H, d,J=13.5 Hz), 7.27 (1H, d, J=8.5 Hz), 7.16 (1H, t, J=8.5 Hz), 6.97 (2H, d,J=8.5 Hz), 4.45 (1H, m), 4.23 (1H, m), 4.10 (1H, m), 3.86 (3H, m), 3.46(2H, m), 3.30 (2H, m), 3.13-3.06 (3H, m), 2.13 (1H, m), 2.04-1.86 (5H,m), 1.82-1.70 (2H, m) ppm.

Example 164: Synthesis of(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(piperidin-1-yl)phenylamino)pyrazine-2-carboxamide(203)

In a similar manner as described in Example 110,(R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(piperidin-1-yl)phenylamino)pyrazine-2-carboxamide(203) was prepared using 4-(piperidin-1-yl)aniline. MS found forC₂₉H₃₅N₇O₃ as (M+H)⁺ 530.4. UV: λ=261, 285, 308, 335, 369 nm. NMR(CD₃OD): δ 7.83 (4H, m), 7.76 (1H, s), 7.49 (2H, d, J=9.0 Hz), 7.00 (2H,d, J=9.0 Hz), 4.52 (1H, m), 4.17 (1H, m), 4.13 (1H, m), 3.86 (3H, m),3.46 (2H, m), 3.22 (1H, m), 2.13 (1H, m), 2.01-1.94 (6H, m), 1.84-1.69(3H, m) ppm.

Example 165: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The mixture of (R)-tert-butyl1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 240 mg,0.71 mmol), 4-(1-methylpiperidin-4-yl)aniline (280 mg, 1.42 mmol),fine-powder cesium carbonate (930 mg, 2.84 mmol), Pd(OAc)₂ (32 mg, 0.14mmol), BINAP (88 mg, 0.14 mmol) in 20 mL dioxane was degassed withnitrogen stream for 3 min. It was then stirred in 115° C. bath innitrogen atmosphere for 2 hours. The mixture was cooled to RT, dilutedwith 100 mL EtOAc, and filtered. The filtrate was concentrated in vacuoand subjected to silica flash column using 0 to 15% MeOH in chloroformto isolate (R)-tert-butyl1-(5-cyano-6-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate(204) in >90% yield. It was dissolved in 30 mL MeOH and 3 mL DMSO. To itwere added two NaOH solid bead (about 200 mg) and then 1 mL 30% H₂O₂.The mixture was stirred at RT for 2 hours, diluted with 10 mL MeCN,stirred for 5 min, and concentrated on rotavap. The residue was dilutedwith 120 mL EtOAc, washed with water, concentrated in vacuo to drynessto give crude (R)-tert-butyl1-(5-carbamoyl-6-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate(205). It was treated with 40 mL commercial 4N HCl in dioxane for 40min, and concentrated in vacuo to afford crude(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(206) hydrochloride. Crude 206 hydrochloride (60 mg, 0.12 mmol) wasdissolved in 3 mL DMF. To it were added DIEA (210 μL, 1.2 mmol) anddimethylcarbamoyl chloride (34 μL, 0.36 mmol). The mixture was stirredat RT for 1.5 hour, acidified with 0.3 mL TFA, and directly subjected toreverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobilephases to isolate(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(207) as HCl salt (36 mg). MS found for C₂₅H₃₆N₈O₂ as (M+H)⁺ 481.2,(M−H)⁻ 479.3. UV: λ=268, 277, 306, 336, 372 nm.

Example 166: Synthesis of(R)-5-(3-(3-ethyl-3-methylureido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 165,(R)-5-(3-(3-ethyl-3-methylureido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(208) was prepared using ethyl(methyl)carbamic chloride. MS found forC₂₆H₃₈N₈O₂ as (M+H)⁺ 495.2, (M−H)⁻ 493.3. UV: λ=268, 277, 306, 336, 373nm.

Example 167: Synthesis of(R)-5-(3-(3,3-diethylureido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 165,(R)-5-(3-(3,3-diethylureido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(209) was prepared using diethylcarbamic chloride. MS found forC₂₇H₄₀N₈O₂ as (M+H)⁺ 509.2, (M−H)⁻ 507.4. UV: λ=267, 277, 306, 336, 372nm.

Example 168: Synthesis of(R)-5-(3-(4-fluorobenzamido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 165,(R)-5-(3-(4-fluorobenzamido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(210) was prepared using 4-fluorobenzoyl chloride. MS found forC₂₉H₃₄FN₇O₂ as (M+H)⁺ 532.1, (M−H)⁻ 530.3. UV: λ=266, 276, 305, 336, 372nm.

Example 169: Synthesis of(R)-5-(3-(4-ethoxybenzamido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 165,((R)-5-(3-(4-ethoxybenzamido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(210) was prepared using 4-ethoxybenzoic acid and PyBOP. MS found forC₃₁H₃₉N₇O₃ as (M+H)⁺ 558.2, (M−H)⁻ 556.3. UV: λ=259, 280, 305, 336, 372nm.

Example 170: Synthesis of(R)-3-(4-(1-(dimethylcarbamoyl)piperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

(R)-5-(3-(3,3-Dimethylureido)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(189) TFA salt (115 mg, 0.20 mmol) was dissolved in 4 mL NMP. To it wereadded DIEA (350 μL, 2.0 mmol) and then dimethylcarbamoyl chloride (55μL, 0.60 mmol). The mixture was stirred at RT for 30 min, quenched with0.5 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mMHCl (aq) and neat MeCN as mobile phases to isolate(R)-3-(4-(1-(dimethylcarbamoyl)piperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(207) as HCl salt (90 mg). MS found for C₂₇H₃₉N₉O₃ as (M+H)⁺ 538.7,(M−H)⁻ 536.3. UV: λ=267, 276, 305, 336, 373 nm. Proton NMR (CD₃OD): δ7.62 (1H, s), 7.55 (2H, d, J=8.5 Hz), 7.17 (2H, d, J=8.5 Hz), 4.33 (1H,m), 4.20 (1H, m), 3.80-3.73 (3H, m), 3.19 (1H, m), 3.09 (1H, m), 2.93(2H, m), 2.89 (6H, s), 2.88 (6H, s), 2.67 (1H, m) 2.02 (1H, m),1.88-1.82 (3H, m), 1.72-1.62 (4H, m) ppm.

Example 171: Synthesis of(R)-3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 170,(R)-3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(213) was prepared using cyclopropanecarbonyl chloride. MS found forC₂₈H₃₈N₈O₃ as (M+H)⁺ 535.7, (M−H)⁻ 533.3. UV: λ=268, 277, 305, 336, 372nm. Proton NMR (CD₃OD): δ 7.62 (1H, s), 7.56 (2H, d, J=8.5 Hz), 7.18(2H, d, J=8.5 Hz), 4.65 (1H, m), 4.46 (1H, m), 4.35 (1H, m), 4.20 (1H,m), 3.76 (1H, m), 3.28 (1H, m), 3.17 (1H, m), 3.08 (1H, m), 2.88 (6H,s), 2.79 (1H, m), 2.75 (1H, m), 2.02 (2H, m), 1.96 (1H, m), 1.87 (2H,m), 1.70-1.55 (4H, m), 0.89 (2H, m), 0.82 (2H, m) ppm.

Example 172: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-(methylsulfonyl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 170,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-(methylsulfonyl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(214) was prepared using methanesulfonyl chloride. MS found forC₂₅H₃₆N₈O₄S as (M+H)⁺ 545.6, (M−H)⁻ 543.2. UV: λ=268, 276, 305, 336, 372nm. Proton NMR (CD₃OD): δ 7.63 (1H, s), 7.56 (2H, d, J=8.5 Hz), 7.19(2H, d, J=8.5 Hz), 4.35 (1H, m), 4.21 (1H, m), 3.84 (2H, m), 3.76 (1H,m), 3.20 (1H, m), 3.10 (1H, m), 2.89 (6H, s), 2.86 (3H, s), 2.85-2.80(2H, m), 2.64 (1H, m), 2.05 (1H, m), 1.96 (2H, m), 1.88 (1H, m), 1.78(2H, m), 1.66 (2H, m) ppm.

Example 173: Synthesis of(R)-3-(4-(1-(N,N-dimethylsulfamoyl)piperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 170,(R)-3-(4-(1-(N,N-dimethylsulfamoyl)piperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(215) was prepared using dimethylsulfamoyl chloride. MS found forC₂₆H₃₉N₉O₄S as (M+H)⁺ 571.8, (M−H)⁻ 569.3. UV: λ=266, 276, 305, 335, 373nm.

Example 174: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-(pyridin-2-yl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide

(R)-5-(3-(3,3-Dimethylureido)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(189) HCl salt (44 mg, 0.082 mmol) was dissolved in 4 mL NMP in a sealedtube. To it were added DIEA (150 μL, 0.82 mmol) and then2-fluoropyridine (35 μL, 0.41 mmol). The mixture was stirred at 120° C.for 3 hours, quenched with 0.5 mL TFA, and directly subjected to reversephase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases toisolate(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-(pyridin-2-yl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(216) as HCl salt. MS found for C₂₉H₃₇N₉O₂ as (M+H)⁺ 544.4. UV: λ=307,344, 370 nm.

Example 175: Synthesis of(R)-3-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

(R)-5-(3-(3,3-Dimethylureido)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(189) TFA salt (115 mg, 0.20 mmol) was dissolved in 10 mL dioxane and 10mL 1,2-dichloroethane (DCE) with DIEA (175 μL, 1.0 mmol). To it wasadded cyclobutanone (450 μL, 6.0 mmol), and the mixture was stirred atRT for overnight. To it were added HOAc (112 μL, 2.0 mmol) and thenNaBH(OAc)₃ (212 mg, 1.0 mmol). The mixture was stirred at RT for 2hours, diluted with 10 mL MeOH, concentrated in vacuo, acidified with0.5 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mMHCl (aq) and neat MeCN as mobile phases to isolate(R)-3-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(217) as HCl salt (73 mg). MS found for C₂₈H₄₀N₈O₂ as (M+H)⁺ 521.7,(M−H)⁻ 519.3. UV: λ=268, 277, 306, 336, 373 nm. Proton NMR (CD₃OD): δ7.65 (1H, s), 7.61 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.29 (1H,m), 4.20 (1H, m), 3.78 (1H, m), 3.70 (1H, m), 3.60 (1H, s), 3.57 (1H,s), 3.30-3.20 (2H, m), 2.92 (2H, m), 2.87 (6H, s), 2.86 (1H, m), 2.37(2H, m), 2.27 (2H, m), 2.14 (2H, m), 2.03 (1H, m), 1.90 (5H, m), 1.67(2H, m) ppm.

Example 176: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 175,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(218) was prepared using dihydro-2H-pyran-4(3H)-one. MS found forC₂₉H₄₂N₈O₃ as (M+H)⁺ 551.5. UV: λ=268, 277, 306, 336, 373 nm. Compound219,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-(2-(2-hydroxyethoxy)ethyl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide,was also found and isolated as a by-product.

Example 177: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-(2-(2-hydroxyethoxy)ethyl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide

(R)-5-(3-(3,3-Dimethylureido)piperidin-1-yl)-3-(4-(1-(2-(2-hydroxyethoxy)ethyl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(219) was found and isolated as a by-product in the final step for thepreparation of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(218). MS found for C₂₈H₄₂N₈O₄ as (M+H)⁺ 555.6, (M−H)⁻ 553.3. UV: λ=268,277, 306, 336, 373 nm.

Example 178: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 175,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(220) was prepared using 3-oxetanone. MS found for C₂₇H₃₈N₈O₃ as (M+H)⁺523.8, (M−H)⁻ 521.3. UV: λ=268, 277, 306, 336, 373 nm. Proton NMR(CD₃OD): δ 7.63 (1H, s), 7.56 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz),4.75 (2H, t, J=7.0 Hz), 4.68 (2H, t, J=6.5 Hz), 4.31 (1H, m), 4.21 (1H,m), 3.74 (2H, m), 3.22 (1H, m), 3.16 (1H, m), 3.05 (2H, m), 2.88 (6H,s), 2.60 (1H, m), 2.21 (2H, m), 2.02 (1H, m), 1.94-1.78 (5H, m), 1.64(2H, m) ppm.

Example 179: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-fluorophenylamino)pyrazine-2-carboxamide

(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate(87, 2.00 g, 5.93 mmol) was treated with 25 mL commercial 4N HCl indioxane at RT for 2 hours. It was concentrated in vacuo to afford crude(R)-5-(3-aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile (221)hydrochloride as white solid. It was dissolved in 10 mL DMF and 50 mLdioxane. To it were added DIEA (8.25 mL, 47.4 mmol) and then dropwisedimethylcarbamoyl chloride (1.64 mL, 17.8 mmol). The mixture was stirredat RT for 3 hours. It was concentrated in vacuo, diluted with 200 mLEtOAc, washed with water ×2, dried, concentrated in vacuo, subjected tosilica flash column using 0 to 4% MeOH in DCM to isolate(R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea(222) (1.47 g, 80%) as a white solid.

(R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea(222, 40 mg, 0.13 mmol), 4-fluoroaniline (29 mg, 0.26 mmol), fine-powdercesium carbonate (170 mg, 0.52 mmol), Pd(OAc)₂ (10 mg, 0.04 mmol), BINAP(25 mg, 0.04 mmol) in 15 mL dioxane was degassed with nitrogen streamfor 3 min. It was then stirred in 115° C. bath in nitrogen atmospherefor 1 hour. The mixture was cooled to RT, diluted with 60 mL EtOAc, andfiltered. The filtrate was concentrated in vacuo and subjected to silicaflash column using 0 to 7% MeOH in chloroform to isolate(R)-3-(1-(5-cyano-6-(4-fluorophenylamino)pyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea(223). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were addedone NaOH solid bead (about 100 mg) and then 0.5 mL 30% H₂O₂. The mixturewas stirred at RT for 1.5 hour, diluted with 10 mL MeCN, stirred for 5min, concentrated in vacuo, acidified with 0.2 mL TFA, and directlysubjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCNas mobile phases to isolate(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-fluorophenylamino)pyrazine-2-carboxamide(224) as HCl salt (40 mg, 76%). MS found for C₁₉H₂₄FN₇O₂ as (M+H)⁺402.1, (M−H)⁻ 400.1. UV: λ=264, 274, 300, 331, 372 nm. Proton NMR(CD₃OD): δ 7.63 (1H, s), 7.59 (2H, m), 7.02 (2H, t, J=9.0 Hz), 4.34 (1H,m), 4.19 (1H, m), 3.74 (1H, m), 3.17 (1H, m), 3.05 (1H, m), 2.89 (6H,s), 2.02 (1H, m), 1.86 (1H, m), 1.70-1.61 (2H, m) ppm.

Example 180: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(phenylamino)pyrazine-2-carboxamide(225) was prepared using aniline. MS found for C₁₉H₂₅N₇O₂ as (M+H)⁺384.4, (M−H)⁻ 382.1. UV: λ=266, 276, 306, 333, 372 nm. Proton NMR(CD₃OD): δ 7.64 (1H, s), 7.60 (2H, d, J=8.0 Hz), 7.28 (2H, t, J=8.5 Hz),6.98 (1H, t, J=7.5 Hz), 4.32 (1H, m), 4.21 (1H, m), 3.75 (1H, m), 3.20(1H, m), 3.13 (1H, m), 2.88 (6H, s), 2.02 (1H, m), 1.86 (1H, m),1.70-1.60 (2H, m) ppm.

Example 181: Synthesis of(R)-3-(4-chlorophenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(4-chlorophenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(226) was prepared using 4-chloroaniline. MS found for C₁₉H₂₄ClN₇O₂ as(M+H)⁺ 418.1 (chloro pattern), (M−H)⁻ 416.1 (chloro pattern). UV: λ=269,278, 306, 335, 370 nm. Proton NMR (CD₃OD): δ 7.65 (1H, s), 7.60 (2H, d,J=9.0 Hz), 7.26 (2H, d, J=9.0 Hz), 4.37 (1H, m), 4.19 (1H, m), 3.75 (1H,m), 3.19 (1H, m), 3.05 (1H, m), 2.89 (6H, s), 2.02 (1H, m), 1.87 (1H,m), 1.70-1.60 (2H, m) ppm.

Example 182: Synthesis of(R)-3-(4-chloro-3-methoxyphenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(4-chloro-3-methoxyphenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(227) was prepared using 4-chloro-3-methoxyaniline. MS found forC₂₀H₂₆ClN₇O₃ as (M+H)⁺ 448.1 (chloro pattern), (M−H)⁻ 446.1 (chloropattern). UV: λ=267, 277, 308, 339, 373 nm.

Example 183: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(3-methoxy-4-methylphenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(3-methoxy-4-methylphenylamino)pyrazine-2-carboxamide(228) was prepared using 3-methoxy-4-toluidine. MS found for C₂₁H₂₉N₇O₃as (M+H)⁺ 428.3. UV: λ=267, 277, 308, 339, 373 nm.

Example 184: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(5-fluoro-6-methylpyridin-2-ylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(5-fluoro-6-methylpyridin-2-ylamino)pyrazine-2-carboxamide(229) was prepared using 2-amino-5-fluoro-6-methylpyridine. MS found forC₁₉H₂₅FN₈O₂ as (M+H)⁺ 417.4, (M−H)⁻ 415.1. UV: λ=268, 271, 296, 303,311, 334, 366 nm.

Example 185: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-ylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-ylamino)pyrazine-2-carboxamide(230) was prepared using 4-amino-1-methylpyridin-2(1H)-one. MS found forC₁₉H₂₆N₈O₃ as (M+H)⁺ 415.2, (M−H)⁻ 413.2. UV: λ=279, 291, 315, 344, 364nm.

Example 186: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)pyrazine-2-carboxamide(231) was prepared using 5-amino-1-methylpyridin-2(1H)-one. MS found forC₁₉H₂₆N₈O₃ as (M+H)⁺ 415.2, (M−H)⁻ 413.1. UV: λ=300, 335, 369 nm.

Example 187: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carboxamide(232) was prepared using 5-amino-3-methylisothiazole hydrochloride. MSfound for C₁₇H₂₄N₈O₂S as (M+H)⁺ 405.3, (M−H)⁻ 403.1. UV: λ=280, 286,315, 344, 368 nm. Proton NMR (CD₃OD): δ 7.91 (1H, s), 6.92 (1H, s), 4.45(1H, m), 4.38 (1H, m), 3.80 (1H, m), 3.33 (1H, m), 3.21 (1H, m), 2.90(6H, s), 2.49 (3H, s), 2.08 (1H, m), 1.97 (1H, m), 1.74 (2H, m) ppm.

Example 188: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-isopropoxyphenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-isopropoxyphenylamino)pyrazine-2-carboxamide(233) was prepared using 4-isopropoxyaniline. MS found for C₂₂H₃₁N₇O₃ as(M+H)⁺ 442.4, (M−H)⁻ 440.2. UV: λ=269, 275, 304, 339, 373 nm. Proton NMR(CD₃OD): δ 7.59 (1H, s), 7.48 (2H, d, J=9.0 Hz), 6.85 (2H, d, J=9.0 Hz),4.52 (1H, m), 4.32 (1H, m), 4.18 (1H, m), 3.74 (1H, m), 3.18 (1H, m),3.09 (1H, m), 2.88 (6H, s), 2.02 (1H, m), 1.85 (1H, m), 1.67 (2H, m),1.30 (6H, d, J=6.0 Hz) ppm.

Example 189: Synthesis of(R)-3-(4-(cyclopentyloxy)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(4-(cyclopentyloxy)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(234) was prepared using 4-cyclopentoxyaniline. MS found for C₂₄H₃₃N₇O₃as (M+H)⁺ 468.4. UV: λ=270, 276, 304, 340, 373 nm.

Example 190: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(2-methoxyethoxy)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(2-methoxyethoxy)phenylamino)pyrazine-2-carboxamide(235) was prepared using 4-(2-methoxyethoxy)aniline. MS found forC₂₂H₃₁N₇O₄ as (M+H)⁺ 458.2, (M−H)⁻ 456.2. UV: λ=270, 275, 303, 339, 373nm.

Example 191: Synthesis of(R)-3-(4-(2-(dimethylamino)ethoxy)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(4-(2-(dimethylamino)ethoxy)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(236) was prepared using 4-(2-(dimethylamino)ethoxy)aniline. MS foundfor C₂₃H₃₄N₈O₃ as (M+H)⁺ 471.3. UV: λ=270, 275, 304, 337, 373 nm.

Example 192: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-nitrophenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-nitrophenylamino)pyrazine-2-carboxamide(237) was prepared using 4-nitroaniline. MS found for C₁₉H₂₄N₈O₄ as(M+H)⁺ 429.1, (M−H)⁻ 427.1. UV: λ=283, 308, 359 nm. Proton NMR (CD₃OD):δ 8.20 (2H, d, J=9.5 Hz), 7.85 (2H, d, J=9.0 Hz), 7.77 (1H, s), 4.53(1H, m), 4.22 (1H, m), 3.78 (1H, m), 3.21 (1H, m), 3.01 (1H, m), 2.93(6H, s), 2.05 (1H, m), 1.93 (1H, m), 1.68 (2H, m) ppm.

Example 193: Synthesis of(R)-3-(4-((dimethylamino)methyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(4-((dimethylamino)methyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(238) was prepared using 4-((dimethylamino)methyl)aniline. MS found forC₂₂H₃₂N₈O₂ as (M+H)⁺ 441.3. UV: λ=271, 282, 310, 337, 372 nm.

Example 194: Synthesis of(R)-3-(4-(dimethylcarbamoyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(4-(dimethylcarbamoyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(239) was prepared using 4-amino-N,N-dimethylbenzamide. MS found forC₂₂H₃₀N₈O₃ as (M+H)⁺ 455.6, (M−H)⁻ 453.2. UV: λ=278, 288, 312, 343, 372nm. Proton NMR (CD₃OD): δ 7.73 (2H, d, J=9.0 Hz), 7.70 (1H, s), 7.42(2H, d, J=8.5 Hz), 4.38 (1H, m), 4.23 (1H, m), 3.76 (1H, m), 3.20 (1H,m), 3.09 (7H, s), 2.89 (6H, s), 2.03 (1H, m), 1.89 (1H, m), 1.69 (2H, m)ppm.

Example 195: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(pyrrolidine-1-carbonyl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(pyrrolidine-1-carbonyl)phenylamino)pyrazine-2-carboxamide(240) was prepared using (4-aminophenyl)(pyrrolidin-1-yl)methanone. MSfound for C₂₄H₃₂N₈O₃ as (M+H)⁺ 481.5, (M−H)⁻ 479.2. UV: λ=280, 286, 315,345, 370 nm.

Example 196: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(pyridin-2-ylcarbamoyl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(pyridin-2-ylcarbamoyl)phenylamino)pyrazine-2-carboxamide(241) was prepared using 4-amino-N-(pyridin-2-yl)benzamide. MS found forC₂₅H₂₉N₉O₃ as (M+H)⁺ 504.2, (M−H)⁻ 502.2. UV: λ=288, 299, 343 nm.

Example 197: Synthesis of(R)-3-(4-(2-cyanopropan-2-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(4-(2-cyanopropan-2-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(242) was prepared using 2-(4-aminophenyl)-2-methylpropanenitrile. MSfound for C₂₃H₃₀N₈O₂ as (M+H)⁺ 451.5, (M−H)⁻ 449.2. UV: λ=268, 278, 306,335, 372 nm. Proton NMR (CD₃OD): δ 7.69 (2H, d, J=9.0 Hz), 7.66 (1H, s),7.44 (2H, d, J=9.0 Hz), 4.43 (1H, m), 4.21 (1H, m), 3.77 (1H, m), 3.19(1H, m), 3.05 (7H, s), 2.90 (6H, s), 2.03 (1H, m), 1.89 (1H, m), 1.71(6H, s), 1.66 (2H, m) ppm. In the final step,(R)-3-(4-(1-amino-2-methyl-1-oxopropan-2-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(243) was also found and isolated as the main by-product.

Example 198: Synthesis of(R)-3-(4-(1-amino-2-methyl-1-oxopropan-2-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

(R)-3-(4-(1-Amino-2-methyl-1-oxopropan-2-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(243) was found and isolated as the main by-product in the final stepduring preparation of(R)-3-(4-(2-cyanopropan-2-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(242). MS found for C₂₃H₃₂N₈O₃ as (M+H)⁺ 469.4, (M−H)⁻467.2. UV: 269,278, 307, 336, 372 nm. Proton NMR (CD₃OD): δ 7.63 (1H, s), 7.61 (2H, d,J=8.5 Hz), 7.33 (2H, d, J=9.0 Hz), 4.40 (1H, m), 4.22 (1H, m), 3.76 (1H,m), 3.18 (1H, m), 3.05 (7H, s), 2.90 (6H, s), 2.02 (1H, m), 1.88 (1H,m), 1.68 (2H, m), 1.54 (6H, s) ppm.

Example 199: Synthesis of(R)-3-(4-(1-cyanocyclopropyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(4-(1-cyanocyclopropyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(244) was prepared using 1-(4-aminophenyl)cyclopropanecarbonitrile. MSfound for C₂₃H₂₈N₈O₂ as (M+H)⁺ 449.4, (M−H)⁻ 447.1. UV: λ=270, 279, 308,337, 372 nm. Proton NMR (CD₃OD): δ 7.65 (1H, s), 7.64 (2H, d, J=9.0 Hz),7.26 (2H, d, J=9.0 Hz), 4.41 (1H, m), 4.20 (1H, m), 3.76 (1H, m), 3.18(1H, m), 3.05 (1H, m), 2.91 (6H, s), 2.03 (1H, m), 1.88 (1H, m), 1.66(4H, m), 1.43 (2H, m) ppm. In the final step,(R)-3-(4-(1-carbamoylcyclopropyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(245) was also found and isolated as the main by-product.

Example 200: Synthesis of(R)-3-(4-(1-carbamoylcyclopropyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

(R)-3-(4-(1-Carbamoylcyclopropyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(243) was found and isolated as the main by-product in the final stepduring preparation of(R)-3-(4-(1-cyanocyclopropyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(244). MS found for C₂₃H₃₀N₈O₃ as (M+H)⁺ 467.3, (M−H)⁻465.2. UV: 270,279, 307, 336, 372 nm. Proton NMR (CD₃OD): δ 7.66 (1H, s), 7.66 (2H, d,J=9.0 Hz), 7.35 (2H, d, J=8.5 Hz), 4.43 (1H, m), 4.23 (1H, m), 3.76 (1H,m), 3.19 (1H, m), 3.05 (1H, s), 2.90 (6H, s), 2.03 (1H, m), 1.89 (1H,m), 1.66 (2H, m), 1.49 (2H, m), 1.08 (2H, m) ppm.

Example 201: Synthesis of(R)-3-(4-(1-(aminomethyl)cyclopropyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

(R)-3-(4-(1-Cyanocyclopropyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(244, 25 mg, 0.05 mmol) was dissolved in 5 mL MeOH. To it were addedCoCl₂ (20 mg, 0.15 mmol) and then NaBH₄ (19 mg, 0.5 mmol). The mixtureimmediately turned black. It was stirred at RT for 15 min, and quenchedwith 1 mL MeCN and 0.5 mL TFA. The mixture was stirred at RT for 10 min,filtered, and directly subjected to reverse phase prep HPLC using 5 mMHCl (aq) and neat MeCN as mobile phases to isolate(R)-3-(4-(1-(aminomethyl)cyclopropyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(246) as HCl salt. MS found for C₂₃H₃₂N₈O₂ as (M+H)⁺ 453.3. UV: λ=269,278, 307, 336, 373 nm.

Example 202: Synthesis of(R)-3-(4-(1-(dimethylcarbamoyl)cyclopropyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

1-(4-Bromophenyl)cyclopropanecarboxylic acid (247, 1.00 g, 4.15 mmol)was dissolved in 10 mL DMF and 90 mL dioxane. To it were addeddimethylamine (2M in THF, 10.4 mL, 20.7 mmol) and then PyBOP (4.32 g,8.30 mmol). The mixture was stirred at RT for 2 hours, concentrated invacuo, diluted with 100 mL EtOAc, washed with water ×3, dried,concentrated in vacuo, and subjected to silica flash column using 0 to3% MeOH in DCM to isolate1-(4-bromophenyl)-N,N-dimethylcyclopropanecarboxamide (248) inquantitative yield. It was dissolved in 100 mL dioxane. To the solutionwere added tert-butyl carbamate (2.91 g, 24.9 mmol), Pd₂(dba)₃ (760 mg,0.83 mmol), XantPhos (1.44 g, 2.49 mmol), fine-powder cesium carbonate(8.12 g, 24.9 mmol). The mixture was degassed using N₂ stream for 5 min,and stirred under N₂ atmosphere at 115° C. for 2 days. It was cooled toRT, concentrated in vacuo, diluted with 200 mL EtOAc, washed with water×3, dried, concentrated, and subjected to silica flash column to isolatetert-butyl 4-(1-(dimethylcarbamoyl)cyclopropyl)phenylcarbamate (249, 600mg). It was treated with 20 mL commercial 4N HCl in dioxane at RT for1.5 hour. The mixture was concentrated in vacuo to dryness to give1-(4-aminophenyl)-N,N-dimethylcyclopropanecarboxamide (250) as HCl salt.

In a similar manner as described in Example 179,(R)-3-(4-(1-(dimethylcarbamoyl)cyclopropyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(251) was prepared using1-(4-aminophenyl)-N,N-dimethylcyclopropanecarboxamide (250). MS foundfor C₂₅H₃₄N₈O₃ as (M+H)⁺ 495.4, (M−H)⁻ 493.2. UV: λ=271, 279, 308, 338,372 nm. Proton NMR (CD₃OD): δ 7.64 (1H, s), 7.59 (2H, d, J=8.5 Hz), 7.11(2H, d, J=8.5 Hz), 4.37 (1H, m), 4.20 (1H, m), 3.75 (1H, m), 3.19 (1H,m), 3.07 (1H, s), 2.96 (6H, s), 2.89 (6H, s), 2.03 (1H, m), 1.87 (1H,m), 1.67 (2H, m), 1.33 (2H, m), 1.20 (2H, m) ppm.

Example 203: Synthesis of(R)-3-(4-(1-cyanocyclopentyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(4-(1-cyanocyclopentyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(252) was prepared using 1-(4-aminophenyl)cyclopentanecarbonitrile. MSfound for C₂₅H₃₂N₈O₂ as (M+H)⁺ 477.5, (M−H)⁻ 475.2. UV: λ=269, 279, 307,335, 373 nm. Proton NMR (CD₃OD): δ 7.68 (2H, d, J=8.5 Hz), 7.66 (1H, s),7.42 (2H, d, J=8.5 Hz), 4.42 (1H, m), 4.21 (1H, m), 3.76 (1H, m), 3.19(1H, m), 3.06 (1H, m), 2.90 (6H, s), 2.42 (2H, m), 2.13 (2H, m),2.04-1.97 (5H, m), 1.88 (1H, m), 1.67 (2H, m) ppm.

Example 204: Synthesis of(R)-3-(4-(1-(aminomethyl)cyclopentyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 201,(R)-3-(4-(1-(aminomethyl)cyclopentyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(253) was prepared using(R)-3-(4-(1-cyanocyclopentyl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(252). MS found for C₂₅H₃₆N₈O₂ as (M+H)⁺481.3. UV: λ=269, 278, 307, 336,372 nm.

Example 205: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1,1-dioxothiomorpholino)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1,1-dioxothiomorpholino)phenylamino)pyrazine-2-carboxamide(254) was prepared using 4-(1,1-dioxothiomorpholino)aniline. MS foundfor C₂₃H₃₂N₈O₄S as (M+H)⁺ 517.4, (M−H)⁻ 515.2. UV: λ=310, 349, 374 nm.

Example 206: Synthesis of(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

4-(4-Nitrophenyl)piperidine (1.00 g, 4.85 mmol) was dissolved in 80 mLMeOH and 2 mL HOAc. To it was added (1-ethoxycycloproxy)trimethylsilane,and the mixture was stirred at RT for 40 min. To it was then addedNaBH₃CN (1.83 g, 29.0 mmol), and the mixture was stirred in 65° C. bathfor overnight. It was concentrated in vacuo to dryness, diluted with 120mL EtOAc, washed with 1N NaOH and water ×2, dried, concentrated invacuo, and subjected to silica flash column using 0 to 4% MeOh in DCM toisolate 1-cyclopropyl-4-(4-nitrophenyl)piperidine (256). It wasdissolved in 50 mL EtOAc. To it was added 10% Pd/C (0.5 g), and themixture was hydrogenated using a H₂ balloon at RT for overnight. Themixture was filtered through celite, and concentrated in vacuo to give4-(1-cyclopropylpiperidin-4-yl)aniline (257) (960 mg, 91% overall) as awhite solid.

In a similar manner as described in Example 179,(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(258) was prepared using 4-(1-cyclopropylpiperidin-4-yl)aniline (257).MS found for C₂₇H₃₈N₈O₂ as (M+H)⁺ 507.7, (M−H)⁻ 505.3. UV: λ=268, 277,306, 336, 373 nm. Proton NMR (CD₃OD): δ 7.65 (1H, s), 7.61 (2H, d, J=8.5Hz), 7.20 (2H, d, J=8.5 Hz), 4.29 (1H, m), 4.20 (1H, m), 3.75 (3H, m),3.33 (1H, m), 3.24 (1H, m), 3.19 (1H, m), 2.92-2.80 (8H, m), 2.14 (2H,m), 2.03 (1H, m), 1.96-1.83 (3H, m), 1.66 (2H, m), 1.02 (4H, m) ppm.

Example 207: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin--yl)-3-(4-(1-ethylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

4-(4-Nitrophenyl)piperidine (255, 500 mg g, 2.4 mmol) was dissolved in30 mL MeCN. To it were added DIEA (830 μL, 4.8 mmol) and then EtOTf (460μL, 3.6 mmol). The mixture was stirred at RT for 10 min, and to it wasadded 0.5 mL morpholine. It was concentrated in vacuo and subjected tosilica flash column using 0 to 7% MeOh in DCM to isolate1-ethyl-4-(4-nitrophenyl)piperidine (259). It was dissolved in 40 mLEtOAc. To it was added 10% Pd/C (0.3 g), and the mixture washydrogenated using a H₂ balloon at RT for overnight. The mixture wasfiltered through celite, and concentrated in vacuo to give4-(1-ethylpiperidin-4-yl)aniline (260) (410 mg, 83% overall) as a whitesolid.

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-ethylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(261) was prepared using 4-(1-ethylpiperidin-4-yl)aniline (260). MSfound for C₂₆H₃₈N₈O₂ as (M+H)⁺ 495.6, (M−H)⁻ 493.2. UV: λ=268, 277, 306,336, 373 nm. Proton NMR (CD₃OD): δ 7.63 (1H, s), 7.59 (2H, d, J=8.5 Hz),7.20 (2H, d, J=8.5 Hz), 4.29 (1H, m), 4.21 (1H, m), 3.76 (1H, m), 3.67(2H, m), 3.22-3.05 (6H, m), 2.89 (6H, s), 2.84 (1H, m), 2.12 (2H, m),2.00 (3H, m), 1.87 (1H, m), 1.68 (2H, m), 1.40 (3H, t, J=7.0 Hz) ppm.

Example 208: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-isopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 207,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-isopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(262) was prepared using 2-iodopropane and cesium carbonate to alkylate4-(4-nitrophenyl)piperidine (255) in a sealed tube at 80° C. forovernight. MS found for C₂₇H₄₀N₈O₂ as (M+H)⁺ 509.7, (M−H)⁻ 507.3. UV:λ=268, 277, 306, 336, 373 nm. Proton NMR (CD₃OD): δ 7.64 (1H, s), 7.59(2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.29 (1H, m), 4.21 (1H, m),3.75 (1H, m), 3.56 (3H, m), 3.24-3.12 (4H, m), 2.88 (6H, s), 2.85 (1H,m), 2.13 (2H, m), 2.05 (3H, m), 1.86 (1H, m), 1.67 (2H, m), 1.39 (6H, d,J=7.0 Hz) ppm. In the final step,(R)-4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-1-isopropylpiperidine1-oxide (263) was also found and isolated as a by-product.

Example 209: Synthesis of(R)-4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-1-isopropylpiperidine1-oxide

(R)-4-(4-(3-Carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-1-isopropylpiperidine1-oxide (263) was found and isolated as a by-product in the final stepduring the preparation of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-isopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(262). MS found for C₂₇H₄₀N₈O₃ as (M+H)⁺ 525.4. UV: λ=268, 277, 306,336, 373 nm.

Example 210: Synthesis of(R)-3-(4-(1-cyclohexylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(4-(1-cyclohexylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(264) was prepared using 4-(1-cyclohexylpiperidin-4-yl)aniline. MS foundfor C₃₀H₄₄N₈O₂ as (M+H)⁺ 549.9, (M−H)⁻ 547.4. UV: λ=268, 277, 306, 336,373 nm. Proton NMR (CD₃OD): δ 7.65 (1H, s), 7.60 (2H, d, J=8.5 Hz), 7.20(2H, d, J=8.5 Hz), 4.29 (1H, m), 4.21 (1H, m), 3.76 (1H, m), 3.60 (1H,s), 3.57 (1H, s), 3.24-3.15 (5H, m), 2.86 (6H, s), 2.84 (1H, m), 2.14(4H, m), 2.03-1.95 (5H, m), 1.87 (1H, m), 1.75-1.65 (3H, m), 1.54 (2H,m), 1.43 (2H, m), 1.24 (1H, m) ppm.

Example 211: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-phenylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(1-phenylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(265) was prepared using 4-(1-phenylpiperidin-4-yl)aniline. MS found forC₃₀H₃₈N₈O₂ as (M+H)⁺ 543.9, (M−H)⁻ 541.3. UV: λ=267, 278, 306, 336, 372nm. Proton NMR (CD₃OD): δ 7.72 (2H, d, J=8.0 Hz), 7.65-7.62 (5H, m),7.57 (1H, t, J=7.0 Hz), 7.28 (2H, d, J=8.5 Hz), 4.31 (1H, m), 4.22 (1H,m), 3.80-3.75 (5H, m), 3.23 (1H, m), 3.16 (1H, m), 3.04 (1H, m), 2.89(6H, s), 2.23 (4H, m), 2.03 (1H, m), 1.88 (1H, m), 1.74-1.64 (2H, m)ppm.

Example 212: Synthesis of(R)-3-(4-cyclohexylphenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(4-cyclohexylphenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(266) was prepared using 4-cyclohexylaniline. MS found for C₂₅H₃₅N₇O₂ as(M+H)⁺ 466.5. UV: λ=267, 276, 305, 336, 373 nm.

Example 213: Synthesis of(R)-3-(2-chloro-4-(piperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 162,(R)-3-(2-chloro-4-(piperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(267) was prepared. MS found for C₂₄H₃₃ClN₈O₂ as (M+H)⁺ 501.2 (chloropattern). UV: λ=309, 344, 388 nm.

Example 214: Synthesis of(R)-3-(4-(4-cyclopropylpiperazin-1-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

1-Cyclopropylpiperazine (268, 1.76 g, 14.0 mmol) was dissolved in 15 mLDMF. To it were added 1-fluoro-4-nitrobenzene (1.00 g, 7.0 mmol) andDIEA (1.24 mL, 7.0 mmol). The mixture was stirred at 90° C. forovernight, cooled to RT, diluted with EtOAc, washed with water ×2,dried, concentrated in vacuo, subjected to silica flash column using 0to 40% EtOAc in DCM to isolate 1-cyclopropyl-4-(4-nitrophenyl)piperazine(269). It was dissolved in 2:1 EtOAc/MeOH (80 mL/40 mL), and to it wereadded 40 μL 6N HCl and 10% Pd/C (0.5 g). The mixture was stirred at RTfor overnight under a hydrogen balloon. It was filtered through celite,concentrated in vacuo to dryness to afford4-(4-cyclopropylpiperazin-1-yl)aniline hydrochloride (270, 1.30 g, 73%overall) as an off-white solid.

In a similar manner as described in Example 179,(R)-3-(4-(4-cyclopropylpiperazin-1-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(271) was prepared using 4-(4-cyclopropylpiperazin-1-yl)anilinehydrochloride (270). MS found for C₂₆H₃₇N₉O₂ as (M+H)⁺ 508.5. UV: λ=309,346, 375 nm. Proton NMR (CD₃OD): δ 7.58 (3H, m), 7.03 (2H, m), 4.28 (1H,m), 4.19 (1H, m), 3.76 (2H, m), 3.65-3.50 (5H, m), 3.20 (1H, m), 3.15(1H, m), 2.96 (2H, m), 2.93 (7H, s), 2.02 (1H, m), 1.86 (1H, m), 1.69(2H, m), 1.09-1.00 (4H, m) ppm.

Example 215: Synthesis of(R)-3-(4-(4-cyclopentylpiperazin-1-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 214,(R)-3-(4-(4-cyclopentylpiperazin-1-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(272) was prepared using 1-cyclopentylpiperazine. MS found forC₂₈H₄₁N₉O₂ as (M+H)⁺ 536.3. UV: λ=309, 347, 374 nm.

Example 216: Synthesis of(R)-3-(1-cyclopropyl-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(1-cyclopropyl-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(273) was prepared using 1-cyclopropyl-1H-pyrazol-4-amine. MS found forC₁₉H₂₇N₉O₂ as (M+H)⁺ 414.4, (M−H)⁻ 412.2. UV: λ=254, 270, 298, 331, 376nm. Proton NMR (CD₃OD): δ 7.97 (1H, s), 7.59 (1H, s), 7.55 (1H, s), 4.38(1H, m), 4.19 (1H, m), 3.76 (1H, m), 3.63 (1H, m), 3.21 (1H, m), 3.10(1H, m), 2.87 (6H, s), 2.03 (1H, m), 1.87 (1H, m), 1.67 (2H, m), 1.06(2H, m), 0.99 (2H, m) ppm.

Example 217: Synthesis of(R)-3-(1-cyclopentyl-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 179,(R)-3-(1-cyclopentyl-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(274) was prepared using 1-cyclopentyl-1H-pyrazol-4-amine. MS found forC₂₁H₃₁N₉O₂ as (M+H)⁺ 442.5, (M−H)⁻ 440.2. UV: λ=254, 270, 298, 332, 375nm. Proton NMR (CD₃OD): δ 8.05 (1H, s), 7.60 (1H, s), 7.59 (1H, s), 4.71(1H, m), 4.40 (1H, m), 4.19 (1H, m), 3.76 (1H, m), 3.21 (1H, m), 3.11(1H, m), 2.87 (6H, s), 2.16 (2H, m), 2.04-1.96 (3H, m), 1.87 (3H, m),1.74 (2H, m), 1 (2H, m) ppm.

Example 218: Synthesis of(R)-3-(1-(1-cyclopentylpiperidin-4-yl)-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

The mixture of(R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea(222, 330 mg, 1.07 mmol), tert-butyl4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (275, 426 mg, 1.60mmol), fine-powder cesium carbonate (1.05 g, 3.21 mmol), Pd(OAc)₂ (72mg, 0.32 mmol), BINAP (200 mg, 0.32 mmol) in 60 mL dioxane was degassedwith nitrogen stream for 3 min. It was then stirred in 115° C. bath innitrogen atmosphere for 2 hours. The mixture was cooled to RT, dilutedwith 60 mL EtOAc, and filtered. The filtrate was concentrated in vacuoand subjected to silica flash column using 0 to 6% MeOH in chloroform toisolate (R)-tert-butyl4-(4-(3-cyano-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(276). It was dissolved in 20 mL MeOH and 4 mL DMSO. To it were addedone NaOH solid bead (about 100 mg) and then 0.5 mL 30% H₂O₂. The mixturewas stirred at RT for 2 hours, diluted with 10 mL MeCN, stirred for 5min, concentrated in vacuo, diluted with EtOAc 150 mL, washed with water×3, dried, concentrated in vacuo to afford crude (R)-tert-butyl4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(277).

Crude (R)-tert-butyl4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(277, 108 mg, 0.19 mmol) was treated with 2:1 DCM/TFA at RT for 1 hourand concentrated in vacuo to get(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide(278) TFA salt. It was dissolved in 10 mL DCE and 2 mL NMP. To it wereadded DIEA (330 μL, 1.9 mmol) and cyclopentanone (480 mg, 5.7 mmol). Themixture was stirred at RT for 5 hours, and to it were added HOAc (220μL, 3.8 mmol) and NaBH(OAc)₃ (240 mg, 1.14 mmol). The mixture wasstirred at RT for overnight. It was diluted with 10 mL MeOH,concentrated in vacuo, acidified with 0.3 mL TFA, and directly subjectedto reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobilephases to isolate(R)-3-(1-(1-cyclopentylpiperidin-4-yl)-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(279) as HCl salt (45 mg, 45%). MS found for C₂₆H₄N₁₀O₂ as (M+H)⁺ 525.6,(M−H)⁻ 523.3. UV: λ=254, 270, 297, 331, 374 nm.

Example 219: Synthesis of(R)-3-(1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

Crude (R)-tert-butyl4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(277, 72 mg, 0.13 mmol) was treated with 2:1 DCM/TFA at RT for 1 hourand concentrated in vacuo to get(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide(278) TFA salt. It was dissolved in 4 mL NMP. To it were added DIEA (230μL, 1.3 mmol) and cyclopropanecarbobyl chloride (41 mg, 0.39 mmol). Themixture was stirred at RT for 2 hours, acidified with 0.5 mL TFA, anddirectly subjected to reverse phase prep HPLC using 5 mM HCl (aq) andneat MeCN as mobile phases to isolate(R)-3-(1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(280) as HCl salt (32 mg, 47%). MS found for C₂₅H₃₆N₁₀O₃ as (M+H)⁺525.5, (M−H)⁻ 523.3. UV: λ=253, 269, 298, 331, 374 nm.

In a similar manner as described in Example 179,(R)-3-(4-cyclohexylphenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(266) was prepared using 4-cyclohexylaniline. MS found for C₂₅H₃₅N₇O₂ as(M+H)⁺ 466.5. UV: λ=267, 276, 305, 336, 373 nm.

Example 220: Synthesis of(R)-3-(1-(1-cyclopentylazetidin-3-yl)-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 218,(R)-3-(1-(1-cyclopentylazetidin-3-yl)-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(281) was prepared using tert-butyl3-(4-amino-H-pyrazol-1-yl)azetidine-1-carboxylate. MS found forC₂₄H₃₆N₁₀₀₂ as (M+H)⁺ 497.4, (M−H)⁻ 495.2. UV: λ=253, 269, 298, 330, 372nm.

Example 221: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(289)

At −30° C. and under N₂ atmosphere, to a solution of ethyl4-oxopiperidine-1-carboxylate (282) (6.0 g, 35.1 mmol) in anhydrous Et₂₀(100 mL) was added MeMgBr (3.0 M, 14 mL, 42.1 mmol). The resultingmixture was stirred at 0° C. for 2 hours before being quenched withaqueous NH₄C₁ solution. The mixture was extracted with DCM (30 mL×3).The combined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo and subjected to silica flash columnchromatography using 0 to 50% EtOAc in PE (petroleum ether) to isolateethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (283) (4 g, 61%) as anoil.

At 0° C. under N₂ atmosphere, to a solution of ethyl4-hydroxy-4-methylpiperidine-1-carboxylate (283) (2.4 g, 12.8 mmol) inbromobenzene (20.1 g, 128 mmol) was added trifluoromethanesulfonic acid(19.2 g, 128 mmol). The resulting mixture was stirred at RT for 3 hoursbefore being poured onto ice. The mixture was basified with 1N NaOH andextracted with DCM (20 mL×3). The combined organic layers were washedwith brine, dried, concentrated in vacuo and subjected to silica flashcolumn using 0 to 20% EtOAc in PE to give ethyl4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (284) (3.4 g, 81%) asa light yellow oil.

To a solution of ethyl4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (284) (5.36 g, 16mmol) in EtOH (75 mL) was added KOH (17.9 g, 320 mmol). The resultingmixture was stirred at 80° C. for overnight before being cooled down toRT. The solvent was removed and the residue was partitioned in water (30mL) and DCM (20 mL). The layers were separated and the aqueous layer wasextracted with DCM (10 mL×5). The combined organic layers were washedwith brine, dried, and concentrated in vacuo to give crude4-(4-bromophenyl)-4-methylpiperidine (285) in quantitative yield, whichwas used directly in next step without further purification.

To a solution of 4-(4-bromophenyl)-4-methylpiperidine (285) (4.1 g, 16mmol) in DCM (20 mL) was added (BOC)₂O (5.7 g, 26 mmol). The resultingmixture was stirred at RT for 30 min before being diluted with water (10mL). The mixture was extracted with DCM (10 mL×2). The combine organiclayers were washed with brine, dried, concentrated in vacuo, andsubjected to silica flash column using 0 to 20% EtOAc in PE to givetert-butyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (286) (5g, 88%) as colorless oil.

A sealed tube was charged with tert-butyl4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (286) (2.6 g, 7.37mmol), (dicyclohexylphosphino)biphenyl (65 mg, 0.18 mmol), Pd₂(dba)₃ (68mg, 0.074 mmol) and LiHMDS (1M, 14.7 mL, 14.7 mmol) in anhydrous THF (15mL). The resulting mixture was purged with N₂ stream and stirred in 65°C. bath for overnight.

After being cooled to RT, the mixture was diluted with water (10 mL) andextracted with DCM (5 mL×3). The combined organic layers were washedwith brine, dried, concentrated in vacuo, and subjected to silica flashcolumn chromatography using 0 to 30% EtOAc in PE to afford tert-butyl4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (750 mg, 36%)as a white solid. Proton NMR (CDCl₃): δ 7.13 (2H, d, J=8.5 Hz), 6.69(2H, d, J=8.5 Hz), 3.67-3.57 (2H, m), 3.54-3.44 (2H, m), 3.43-3.33 (2H,m), 2.03 (2H, s), 1.67-1.61 (2H, m), 1.47 (9H, s), 1.22 (3H, s) ppm.

The mixture of3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea(222) (250 mg, 0.81 mmol), tert-butyl4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (400 mg, 1.22mmol), fine-powder cesium carbonate (800 mg, 2.43 mmol), Pd(OAc)₂ (55mg, 0.24 mmol), BINAP (150 mg, 0.24 mmol) in 30 mL dioxane was degassedwith nitrogen stream for 3 min. It was then stirred in 115° C. bath innitrogen atmosphere for 2 hours. The mixture was cooled to RT, dilutedwith 100 mL EtOAc, and filtered using ChemGlass OP-6602-12 disposablefunnel. The filtrate was concentrated in vacuo and subjected to silicaflash column using 0 to 8% MeOH in DCM to isolate (R)-tert-butyl4-(4-(3-cyano-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate(288). It was dissolved in 10 mL MeOH and 3 mL DMSO. To it were addedone NaOH solid bead (about 100 mg) and then 1 mL 30% H₂O₂. The mixturewas stirred at RT for overnight, diluted with 10 mL MeCN, stirred for 5min, and concentrated on rotavap. The residue was diluted with 150 mLEtOAc, washed with water ×3, dried, and subjected to silica flash columnusing 0 to 10% MeOH in DCM to isolate (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate.It was treated with 20 mL commercial 4N HCl in dioxane at RT for 45 min,and concentrated to dryness to give crude(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(289) as HCl salt. It was subjected to reverse phase prep HPLC using 5mM HCl (aq) and neat MeCN as mobile phases for purification. MS foundfor C₂₅H₃₆N₈O₂ as (M+H)⁺ 481.3. UV: λ=268, 277, 306, 336, 373 nm.

Example 222: Synthesis of(R)-3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

(R)-5-(3-(3,3-Dimethylureido)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(289) (190 mg, 0.4 mmol) was dissolved in 20 mL DCE and 20 mL dioxane.To it were added DIEA (350 μL, 2.0 mmol) and cyclopentanone (710 μL, 8.0mmol). The mixture was stirred at RT for 2 hours, and to it were addedHOAc (250 μL, 4.0 mmol) and NaBH(OAc)₃ (430 mg, 2.0 mmol). The mixturewas stirred at RT for 1.5 hour. It was diluted with 10 mL MeOH,concentrated in vacuo, acidified with 0.5 mL TFA, and directly subjectedto reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobilephases to isolate(R)-3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(290) as HCl salt (82 mg, 37%). MS found for C₃₀H₄₄N₈O₂ as (M+H)⁺ 549.6.UV: λ=268, 278, 306, 336, 373 nm. Proton NMR (CD₃OD): δ 7.71-7.63 (3H,m), 7.36-7.33 (2H, m), 4.38-4.32 (1H, m), 4.22 (1H, m), 3.77 (1H, m),3.66-3.50 (2H, m), 3.28-3.10 (2H, m), 2.89 (6H, s), 2.86-2.80 (2H, m),2.64 (1H, m), 2.23-1.62 (16H, m), 1.42-1.26 (3H, s) ppm.

Example 223: Synthesis of(R)-3-(4-(1-(dimethylcarbamoyl)-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

(R)-5-(3-(3,3-Dimethylureido)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(289) (90 mg, 0.2 mmol) was dissolved in 4 mL NMP. To it were added DIEA(350 μL, 2.0 mmol) and then dimethylcarbamoyl chloride (55 μL, 0.6mmol). The mixture was stirred at RT for 30 min, quenched with 0.5 mLTFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl(aq) and neat MeCN as mobile phases to isolate(R)-3-(4-(1-(dimethylcarbamoyl)-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(291) as HCl salt (61 mg, 55%). MS found for C₂₈H₄₁N₉O₃ as (M+H)⁺ 552.4,(M−H)⁻550.3. UV: λ=268, 277, 305, 336, 372 nm. Proton NMR (CD₃OD): δ7.63 (1H, s), 7.61 (2H, d, J=8.5 Hz), 7.32 (2H, d, J=8.5 Hz), 4.37 (1H,m), 4.21 (1H, m), 3.77 (1H, m), 3.37-3.31 (2H, m), 3.21-3.15 (3H, m),3.10 (1H, m), 2.88 (6H, s), 2.83 (6H, s), 2.15 (2H, m), 2.02 (1H, m),1.87 (1H, m), 1.75-1.63 (4H, m), 1.26 (3H, s) ppm.

Example 224: Synthesis of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(4-methyl-1-propionylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

In a similar manner as described in Example 223,(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(4-methyl-1-propionylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(292) was prepared using propionyl chloride. MS found for C₂₈H₄₀N₈O₃ as(M+H)⁺ 537.4, (M−H)⁻ 535.3. UV: λ=268, 277, 306, 336, 372 nm. Proton NMR(CD₃OD): δ 7.63 (1H, s), 7.62 (2H, d, J=8.5 Hz), 7.33 (2H, d, J=8.5 Hz),4.37 (1H, m), 4.20 (1H, m), 3.81-3.77 (2H, m), 3.62 (1H, m), 3.40 (2H,m), 3.20 (1H, m), 3.10 (1H, m), 2.88 (6H, s), 2.42 (2H, m), 2.20-2.11(2H, m), 2.03 (1H, m), 1.88 (1H, m), 1.73 (1H, m), 1.71-1.61 (3H, m),1.27 (3H, s), 1.11 (3H, t, J=7.5 Hz) ppm.

Example 225: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin--ylcarbamate(87, 550 mg, 1.63 mmol) was dissolved in 20 mL DMF. To it was added NaH(60% in mineral oil, 98 mg, 2.45 mmol). The mixture was stirred at RTfor 30 min, and then iodomethane (305 μL, 4.89 mmol) was added. It wasstirred for 1.5 hour, diluted with 120 mL EtOAc, washed with water ×3,dried, concentrated, and subjected to flash column using 0 to 50% EtOAcin hexane to isolate (R)-tert-butyl1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl(methyl)carbamate (293).It was treated with 20 mL commercial 4N HCl in dioxane at RT for 1 hour,and the mixture was concentrated in vacuo to dryness. It was dissolvedin 5 mL DMF and 15 mL dioxane. To it were added DIEA (1.45 mL, 8.15mmol) and then dimethylcarbamoyl chloride (300 μL, 3.26 mmol). Themixture was stirred at RT for overnight, diluted with 120 mL EtOAc,washed with water ×2, dried, concentrated, and subjected to silica flashcolumn using 0 to 5% MeOH in DCM to isolate(R)-1-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,3,3-trimethylurea(294, 490 mg, 93% overall) as a white solid.

The mixture of(R)-1-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,3,3-trimethylurea(294, 390 mg, 1.21 mmol), tert-butyl4-(4-aminophenyl)piperidine-1-carboxylate (670 mg, 2.42 mmol),fine-powder cesium carbonate (1600 mg, 4.84 mmol), Pd(OAc)₂ (134 mg,0.60 mmol), BINAP (374 mg, 0.60 mmol) in 60 mL dioxane was degassed withnitrogen stream for 5 min. It was then stirred in 115° C. bath innitrogen atmosphere for 2 hours. The mixture was cooled to RT, dilutedwith 120 mL EtOAc, and filtered. The filtrate was concentrated in vacuoand subjected to silica flash column using 20 to 100% EtOAc in DCM toisolate (R)-tert-butyl4-(4-(3-cyano-6-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)piperidine-1-carboxylate(295) in >80% yield. It was dissolved in 40 mL MeOH and 10 mL DMSO. Toit were added two NaOH solid bead (about 200 mg) and then 2 mL 30% H₂O₂.The mixture was stirred at RT for 3 hours, diluted with 10 mL MeCN,stirred for 5 min, and concentrated on rotavap. The residue was dilutedwith 120 mL EtOAc, washed with water ×2, concentrated, and subjected tosilica flash column using 0 to 7% MeOh in DCM to give crude(R)-tert-butyl4-(4-(3-carbamoyl-6-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)piperidine-1-carboxylate(296). It was treated with 30 mL commercial 4N HCl in dioxane for 90min, and concentrated in vacuo to afford crude(R)-3-(4-(piperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(297) hydrochloride.

Crude(R)-3-(4-(piperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(297) (100 mg, 0.18 mmol) was dissolved in 10 mL DCE and 10 mL dioxane.To it were added DIEA (160 μL, 0.90 mmol) and cyclopentanone (320 μL,3.60 mmol). The mixture was stirred at RT for 2 hours, and to it wereadded HOAc (100 μL, 1.8 mmol) and NaBH(OAc)₃ (190 mg, 0.90 mmol). Themixture was stirred at RT for overnight. It was diluted with 10 mL MeOH,concentrated in vacuo, acidified with 0.5 mL TFA, and directly subjectedto reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobilephases to isolate(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(298) as HCl salt (29 mg, 29%). MS found for C₃₀H₄₄N₈O₂ as (M+H)⁺ 549.6.UV: λ=269, 276, 306, 335, 373 nm. Proton NMR (CD₃OD): δ 7.64 (1H, s),7.57 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.53 (1H, m), 4.35 (1H,m), 3.72 (1H, s), 3.70 (1H, s), 3.56 (2H, m), 3.20 (1H, m), 3.13 (2H,m), 3.00 (1H, m), 2.85 (1H, m), 2.83 (3H, s), 2.77 (6H, s), 2.21 (2H,m), 2.12 (2H, m), 2.03-1.65 (12H, m) ppm.

Example 226: Synthesis of(R)-3-(4-(1-(dimethylcarbamoyl)piperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 223,(R)-3-(4-(1-(dimethylcarbamoyl)piperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(299) was prepared using(R)-3-(4-(piperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(297). MS found for C₂₈H₄₁N₉O₃ as (M+H)⁺ 552.5. UV: λ=268, 276, 305,336, 373 nm. Proton NMR (CD₃OD): δ 7.61 (1H, s), 7.53 (2H, d, J=8.5 Hz),7.17 (2H, d, J=8.5 Hz), 4.54 (1H, m), 4.34 (1H, m), 3.80 (1H, s), 3.77(1H, s), 3.58 (1H, m), 3.17 (1H, m), 2.98 (1H, m), 2.93 (2H, m), 2.87(6H, s), 2.82 (3H, s), 2.78 (6H, s), 2.65 (1H, m), 2.42 (2H, m),1.98-1.63 (8H, m) ppm.

Example 227: Synthesis of(R)-3-(4-(1-propionylpiperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 226,(R)-3-(4-(1-propionylpiperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(300) was prepared using propionyl chloride. MS found for C₂₈H₄₀N₈O₃ as(M+H)⁺ 537.5. UV: λ=268, 276, 305, 336, 373 nm.

Example 228: Synthesis of(R)-3-(4-(1-(methylsulfonyl)piperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 226,(R)-3-(4-(1-(methylsulfonyl)piperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(301) was prepared using methanesulfonyl chloride. MS found forC₂₆H₃₈N₈O₄S as (M+H)⁺ 559.4. UV: λ=268, 277, 305, 336, 372 nm.

Example 229: Synthesis of(R)-3-(4-(1,1-dioxothiomorpholino)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide

In a similar manner as described in Example 226,(R)-3-(4-(1,1-dioxothiomorpholino)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide(302) was prepared using 4-(1,1-dioxothiomorpholino)aniline. MS foundfor C₂₄H₃₄N₈O₄S as (M+H)⁺ 531.1, (M−H)⁻ 529.3. UV: λ=310, 348, 373 nm.Proton NMR (CD₃OD): δ 7.61 (1H, s), 7.52 (2H, d, J=9.0 Hz), 7.01 (2H, d,J=9.0 Hz), 4.54 (1H, m), 4.34 (1H, m), 3.77 (4H, m), 3.56 (1H, m), 3.20(1H, m), 3.16 (4H, m), 2.99 (1H, m), 2.82 (3H, s), 2.78 (6H, s),2.01-1.88 (3H, m), 1.65 (1H, m) ppm.

Example 230: Synthesis of5-((2R,3R)-3-amino-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

4-(4-Nitrophenyl)piperidine (5 g, 24 mmol) was dissolved in MeOH (240mL). To the solution were added cyclopentanone (6.5 mL, 73 mmol) andacetic acid (3 mL). The mixture was stirred for 1 hour, and then NaBH₃CN(6.1 g, 97 mmol) was added. The mixture was stirred at room temperaturefor 12 hours. The solvent was removed under reduced pressure, and theresidue was suspended in EtOAc. The organic suspension was washed with1N NaOH (aq), water and brine, dried, concentrated and purified by flashcolumn chromatography (MeOH/DCM) to obtain1-cyclopentyl-4-(4-nitrophenyl)piperidine (303) (6.5 g, 24 mmol, 100%yield).

1-Cyclopentyl-4-(4-nitrophenyl)piperidine (303) (6.5 g, 24 mmol) wasdissolved in IPA (70 mL) and 2M HCl (aq) (18 mL), and 10% Pd/C (2 g) wasadded. The resulting mixture was agitated on Parr shaker under 50 psihydrogen for 18 hours. The reaction mixture was filtered through celite,and the solvent was removed under reduced pressure to give4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (4.0 g, 14mmol, 60% yield).

To a 1-liter round bottom flask were added(R)-5-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)pentanoicacid (10 g, 27 mmol), N-methoxy-N-methylamine-HCl (5.3 g, 55 mmol),PyBOP (21 g, 41 mmol), and MeCN (400 mL). DIEA (19 mL, 110 mmol) wasadded and the reaction was allowed to stir at room temperature for 12hours. The solvent was removed under reduced pressure and the residuewas suspended in EtOAc and washed with 1N NaOH (aq) (×3) then 2N HCl(aq) (×2), then saturated NaHCO₃(aq) (×1), then brine (×1). The productwas then purified by column chromatography (EtOAc/hexanes) to giveN-methoxy-N-methyl-(R)-5-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)pentanamide(305) (10.9 g, 26.7 mmol, 99% yield) as a clear oil.

N-Methoxy-N-methyl-(R)-5-(Benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)-pentanamide(305) (10 g, 24 mmol) was dissolved in THF (250 mL) and the solution wascooled to −30° C. in a dry-ice acetone bath. MeMgBr (3M in Et₂O, 123 mL,369 mmol) was added drop-wise over 30 minutes. The bath temperature wasslowly allowed to increase to 0° C. and then was maintained at 0° C.until TLC showed no further reaction progress (˜80-90% complete).Saturated NH₄C₁ (aq) was then slowly added to the reaction mixture at 0°C. and the THF was removed under reduced pressure. The resulting aqueoussolution was then extracted with EtOAc and the extracts were washed withwater and then brine. The residue was then purified by columnchromatography (EtOAc/hexanes) to give(R)-6-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)-2-hexanone(306), (6.5 g, 18 mmol, 75% yield).

(R)-6-(Benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)-2-hexanone(306) (14.3 g, 39.3 mmol) was divided in 2 equal batches and each batchwas dissolved in IPA (70 mL), combined with 10% Pd/C (5.5 g), andhydrogenated on a Parr shaker at 50 psi pressure for 12 hours. Thebatches were combined, filtered through celite and concentrated in vacuoto give (R)-tert-butyl 2-methylpiperidin-3-ylcarbamate (307), (8.2 g, 38mmol, 97% yield) as a clear oil.

(R)-tert-Butyl 2-methylpiperidin-3-ylcarbamate (307) (8.2 g, 38 mmol)was suspended in a solution of DCM (500 mL) and DIEA (13.4 mL, 76.9mmol). Benzyl chloroformate (6.6 mL, 46 mmol) was then added drop-wiseover 5 minutes and the reaction was stirred at 0° C. for 30 minutes.Water was then added and the mixture was allowed to come to roomtemperature and stirred for 30 minutes. The organic phase was separated,washed with 1M HCl (aq), saturated NaHCO₃(aq), and brine. On TLC, thetrans-isomer (309) displayed a higher silica R_(f) value than the cisisomer (308). The two diastereomers were separated by silica flashcolumn chromatography (EtOAc/hexanes). The mixed fractions from thefirst purification were combined and subjected to a second purification.After two purifications, (2R,3R)-benzyl3-(tert-butoxycarbonylamino)-2-methylpiperidine-1-carboxylate (308) (2.5g, 7.2 mmol, 19% yield) and (2S,3R)-benzyl3-(tert-butoxycarbonylamino)-2-methylpiperidine-1-carboxylate (309) (8g, 23 mmol, 61% yield) were obtained.

(2R,3R)-Benzyl3-(tert-butoxycarbonylamino)-2-methylpiperidine-1-carboxylate (308) (1.7g, 4.9 mmol) was dissolved in IPA (20 mL). 10% Pd/C (1 g) was added andthe mixture was hydrogenated on a Parr shaker at 50 psi pressure for 12hours. The reaction mixture was filtered through celite, and the solventwas removed under reduced pressure to give tert-butyl(2R,3R)-2-methylpiperidin-3-ylcarbamate (310), (1.1 g, 5.1 mmol, 100%yield).

tert-Butyl (2R,3R)-2-methylpiperidin-3-ylcarbamate (310) (1.1 g, 5.1mmol) was dissolved in THF (20 mL). To the stirred solution was addedDIEA (1.34 mL, 7.7 mmol), followed by3,5-dichloropyrazine-2-carbonitrile (1.07 g, 6.2 mmol). The reaction wasstirred at room temperature for 1 hour. An additional amount of3,5-dichloropyrazine-2-carbonitrile (200 mg, 1.2 mmol) was added, andthe reaction was stirred for another hour. The solvent was removed underreduced pressure, and the residue was suspended in EtOAc. The organicmixture was washed with 1N HCl (aq), saturated NaHCO₃(aq) and brine,dried, and concentrated in vacuo. The residue was then purified bysilica flash column chromatography (EtOAc/hexanes) to give tert-butyl(2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate(311), (1.54 g, 4.38 mmol, 86% yield).

tert-Butyl(2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate(311) (390 mg, 1.1 mmol), 4-(1-cyclopentylpiperidin-4-yl)aniline HClsalt (304) (406 mg, 1.7 mmol), fine-powder Cs₂CO₃ (1.1 g, 3.3 mmol),BINAP (207 mg, 0.33 mmol), and Pd(OAc)₂ (75 mg, 0.33 mmol) were combinedand suspended in dioxane (30 mL) and water (1 mL). The mixture wassparged with nitrogen stream for 10 minutes, and then stirred undernitrogen atmosphere in 115° C. oil bath for 5 hours. The mixture wascooled to RT, diluted with EtOAc (100 mL), stirred, filtered andconcentrated under reduced pressure. The resulting residue was subjectedto silica flash column chromatography (MeOH/DCM) to give tert-butyl(2R,3R)-1-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate(312) (430 mg, 0.74 mmol, 68% yield).

tert-Butyl(2R,3R)-1-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate(312) (430 mg, 0.74 mmol) was dissolved in MeOH (25 mL), DMSO (4.4 mL),and TEA (0.22 mL, 1.6 mmol). The solution was cooled to 0° C., and apre-mixed solution of 30% H₂O₂ (175 μL, 1.5 mmol) and 4N NaOH (384 μL,1.5 mmol) was added. The reaction was stirred for 1 hour at 0° C. Anadditional amount of the pre-mixed solution 30% H₂O₂ (175 μL, 1.5 mmol)and 4N NaOH (384 μL, 1.5 mmol) was added, and the reaction was stirredfor an additional hour at 0° C. MeCN (10 mL) was then added and thesolution was stirred for 10 minutes at room temperature. The solventswere removed under reduced pressure, and the residue was subjected tosilica flash column chromatography (MeOH/DCM) to give tert-butyl(2R,3R)-1-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate(313) (430 mg, 0.74 mmol, 97% yield).

tert-Butyl(2R,3R)-1-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate(313) (430 mg, 0.74 mmol) was treated in DCM (20 mL) and TFA (7 mL) atroom temperature for 2 hours. The mixture was concentrated in vacuo,dissolved in MeOH/water, and subjected to reverse phase prep HPLC using5 mM HCl in water and neat MeCN as mobile phases to isolate5-((2R,3R)-3-amino-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(314) as HCl salt. LC-MS (ESI): m/z (M+1) 478.5. UV: λ=264, 274, 304,335, 372 nm. Proton NMR (CD₃OD): δ 7.66 (1H, s), 7.58 (2H, d, J=8.5 Hz),7.27 (2H, d, J=8.5 Hz), 5.03 (1H, m), 4.32 (1H, d, J=11.0 Hz), 3.72 (2H,d, J=10.0 Hz), 3.56 (1H, m), 3.45 (1H, m), 3.14 (2H, m), 3.11 (1H, m),2.88 (1H, m), 2.22-1.70 (16H, m), 1.32 (3H, d, J=7.0 Hz) ppm.

Example 231: Synthesis of5-((2S,3R)-3-amino-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,5-((2S,3R)-3-amino-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(315), was prepared by the same synthetic scheme illustrated for Example230 using (2S,3R)-benzyl3-(tert-butoxycarbonylamino)-2-methylpiperidine-1-carboxylate (309). Itwas isolated as HCl salt using reverse phase prep HPLC. LC-MS (ESI): m/z(M+1) 478.4. UV: λ=263, 272, 304, 334, 370 nm. Proton NMR (CD₃OD): δ7.70 (1H, s), 7.59 (2H, d, J=9.0 Hz), 7.26 (2H, d, J=8.5 Hz), 4.89 (1H,m), 4.30 (1H, d, J=13.5 Hz), 3.72 (2H, d, J=10.0 Hz), 3.56 (2H, m), 3.25(1H, m), 3.14 (2H, m), 2.89 (1H, m), 2.24-1.71 (16H, m), 1.39 (3H, d,J=7.0 Hz) ppm.

Example 232: Synthesis of3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

5-((2R,3R)-3-Amino-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(314) (15 mg, 0.027 mmol, HCL salt) was dissolved in 3 mL NMP andstirred at RT. To it were added DIEA (47 μL, 0.27 mmol) and thendimethylcarbamoyl chloride (15 μL, 0.162 mmol). The mixture was stirredfor 1 hour, quenched with TFA (0.1 mL), and directly subjected toreverse phase prep HPLC to isolate3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(316) as HCl salt (14 mg). LC-MS (ESI): m/z (M+1) 549.8. UV: λ=268, 277,306, 336, 373 nm. Proton NMR (CD₃OD): δ 7.65 (1H, s), 7.61 (2H, d, J=8.5Hz), 7.21 (2H, d, J=8.5 Hz), 4.98 (1H, m), 4.35 (1H, m), 3.87 (1H, m),3.71 (2H, d, J=12.5 Hz), 3.54 (1H, m), 3.13 (2H, m), 3.04 (1H, m), 3.02(6H, s), 2.85 (1H, m), 2.23 (2H, m), 2.14 (2H, m), 1.97 (2H, m), 1.88(4H, m), 1.79-1.64 (5H, m), 1.17 (3H, d, J=7.0 Hz) ppm.

Example 233: Synthesis of3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2S,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

The title compound,3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2S,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(317), was prepared by the same synthetic scheme illustrated for Example232 using5-((2S,3R)-3-amino-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(315). LC-MS (ESI): m/z (M+1) 549.8. UV: λ=268, 277, 306, 336, 373 nm.

Example 234: Synthesis of5-((2R,3R)-3-benzamido-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,5-((2R,3R)-3-benzamido-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(318), was prepared by the same synthetic method illustrated for Example232 using benzoyl chloride. LC-MS (ESI): m/z (M+1) 582.8. UV: λ=268,276, 304, 334, 372 nm. Proton NMR (CD₃OD): δ 7.88 (2H, d, J=8.5 Hz),7.66 (1H, s), 7.61 (2H, d, J=8.0 Hz), 7.58 (1H, d, J=7.5 Hz), 7.52 (2H,t, J=7.5 Hz), 7.17 (2H, d, J=8.0 Hz), 5.24 (1H, m), 4.25 (1H, m), 4.21(1H, m), 3.62 (2H, m), 3.54 (1H, m), 3.15 (1H, m), 3.07 (2H, m), 2.80(1H, m), 2.20 (2H, m), 2.04 (3H, m), 1.97 (1H, m), 1.85 (5H, m), 1.74(5H, m), 1.21 (3H, d, J=7.0 Hz) ppm.

Example 235: Synthesis of5-((2S,3R)-3-benzamido-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,5-((2S,3R)-3-benzamido-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(319), was prepared by the same synthetic method illustrated for Example233 using benzoyl chloride. LC-MS (ESI): m/z (M+1) 582.9. UV: λ=267,277, 306, 336, 373 nm.

Example 236: Synthesis of3-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-ethylpiperidin-1-yl)pyrazine-2-carboxamide

The title compound,3-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-ethylpiperidin-1-yl)pyrazine-2-carboxamide(320), was prepared by the same synthetic scheme illustrated for Example232 using commercial EtMgBr reagent and cyclobutanone. LC-MS (ESI): m/z(M+1) 549.6. UV: λ=269, 280, 307, 337, 373 nm.

Example 237: Synthesis of3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

4-(4-Nitrophenyl)piperidine (3.0 g, 14.5 mmol) was dissolved in 200 mLMeOH and 6 mL acetic acid. To it was added(1-ethoxycycloproxy)trimethylsilane (8.8 mL, 43.6 mmol), and the mixturewas stirred at RT for 2 hours. To it was then added NaBH₃CN (5.5 g, 87.3mmol), and the mixture was sent to 65° C. bath with a condenserattached. The reaction was found cleanly complete in 16 hours. Themixture was concentrated on a rotavap, and EtOAc was poured into theresidue. The organic mixture was washed with 1N NaOH and water (×2),dried over MgS₄, concentrated on rotavap and subjected to silica flashcolumn using 0 to 4% MeOH in DCM to isolate1-cyclopropyl-4-(4-nitrophenyl)piperidine (321) as a thick oil. It wasdissolved in 300 mL iPrOH. To it were added 40 μL 6N HC and 10% Pd/C(1.0 g). The mixture was hydrogenated at 40 psi on a Parr shaker for 16hours. It was filtered through celite, and the solid cake was thoroughlyrinsed with MeOH. The filtrate was concentrated in vacuo to yield4-(1-cyclopropylpiperidin-4-yl)aniline (322, HCl salt) as a white solid(3.06 g, 83% for two steps).

Commercial (2R,3R)-benzyl 3-amino-2-methylpiperidine-1-carboxylate (323,CAS: 104461-49-7) (900 mg, 3.63 mmol) was dissolved in 30 mL MeCN andstirred at RT. To it were added DIEA (1.89 mL, 10.89 mmol) and thendrop-wise dimethylcarbamoyl chloride (1.00 mL, 10.89 mmol). The mixturewas stirred for overnight, concentrated on rotavap, diluted with EtOAc,washed with water ×2, dried over MgSO₄, concentrated on rotavap,subjected to silica flash column using 0 to 4% MeOH in DCM to give(2R,3R)-benzyl 3-(3,3-dimethylureido)-2-methylpiperidine-1-carboxylate(324). It was dissolved in 100 mL iPrOH, and subjected to hydrogenationat 35 psi on Parr shaker with 10% Pd/C (1.0 g) for overnight. Themixture was filtered through celite, and the filtrate was concentratedin vacuo to afford 1,1-dimethyl-3-((2R,3R)-2-methylpiperidin-3-yl)urea(325) as a thick oil. It was dissolved in 30 mL dry DMF. To it wereadded 3,5-dichloropyrazine-2-carbonitrile (630 mg, 3.6 mmol) and thenDIEA (1.25 mL, 7.2 mmol). The mixture was stirred at RT for overnight.It was diluted with 300 mL EtOAc, washed with water ×3, dried overMgSO₄, concentrated on rotavap, and subjected to silica flash columnwith 0 to 4% MeOH in DCM to isolate3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea(326) (850 mg, 73% overall yield for three steps).

The mixture of3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea(326) (80 mg, 0.25 mmol), 4-(1-cyclopropylpiperidin-4-yl)aniline (322,HCl salt, 76 mg, 0.30 mmol), fine-powder cesium carbonate (326 mg, 1.00mmol), Pd(OAc)₂ (18 mg, 0.08 mmol), BINAP (50 mg, 0.08 mmol) in 15 mLdioxane was degassed with nitrogen stream for 3 min. It was then stirredin 115° C. bath in nitrogen atmosphere for 3 hours. The mixture wascooled to RT, diluted with 100 mL EtOAc, and filtered using ChemGlassOP-6602-12 disposable funnel. The filtrate was concentrated in vacuo andsubjected to silica flash column using 0 to 5% MeOH in DCM to isolate3-((2R,3R)-1-(5-cyano-6-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea(327). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added100 μL Et₃N, 100 mg powder cesium carbonate, and then 0.5 mL 30% H₂O₂.The mixture was stirred at RT for 1.5 hour, diluted with 10 mL MeCN,stirred for 5 min, concentrated on rotavap. The residue was treated with0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mMHCl (aq) and neat MeCN as mobile phases to isolate3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(328) as HCl salt (76 mg, 58% yield). LC-MS (ESI): m/z (M+1) 521.8. UV:λ=268, 277, 306, 336, 372 nm. Proton NMR (CD₃OD): δ 7.64 (1H, s), 7.61(2H, d, J=8.5 Hz), 7.20 (2H, d, J=8.5 Hz), 4.98 (1H, m), 4.34 (1H, m),3.87 (1H, m), 3.77 (1H, s), 3.74 (1H, s), 3.34 (2H, m), 3.02 (1H, m),2.95 (6H, s), 2.90 (1H, m), 2.85 (1H, m), 2.15 (2H, m), 1.95-1.65 (6H,m), 1.17 (3H, d, J=7.0 Hz), 1.02 (4H, m) ppm.

Example 238: Synthesis of3-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(329)

The title compound,3-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(329), was prepared by the same synthetic scheme illustrated for Example237 using cyclobutanone. LC-MS (ESI): m/z (M+1) 535.8. UV: λ=268, 277,306, 336, 372 nm. Proton NMR (CD₃OD): δ 7.64 (1H, s), 7.61 (2H, d, J=8.5Hz), 7.20 (2H, d, J=8.5 Hz), 4.97 (1H, m), 4.35 (1H, m), 3.87 (1H, m),3.68 (1H, m), 3.59 (1H, s), 3.56 (1H, s), 3.04 (1H, m), 2.96 (6H, s),2.92 (2H, m), 2.84 (1H, m), 2.37 (2H, m), 2.30 (2H, m), 2.13 (2H, m),1.95-1.90 (6H, m), 1.73 (1H, m), 1.66 (1H, m), 1.17 (3H, d, J=7.0 Hz)ppm.

Example 239: Synthesis of5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)-3-(4-(1-(trifluoromethyl)cyclopropyl)phenylamino)pyrazine-2-carboxamide

1-Bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene (1.00 g, 3.77 mmol)was mixed with tert-butyl carbamate (1.77 g, 15.1 mmol), Pd₂(dba)₃ (350mg, 0.38 mmol), XantPhos (650 mg, 1.13 mmol), fine-powder cesiumcarbonate (7.40 g, 22.6 mmol) in 80 mL dioxane. The mixture was degassedusing nitrogen stream for 5 min, and stirred in 115° C. bath undernitrogen atmosphere for 7 hours. It was cooled to RT, diluted with 200mL EtOAc, well stirred, filtered using ChemGlass OP-6602-12 disposablefunnel, concentrated in vacuo, and subjected to silica flash columnusing 0 to 1% MeOH in DCM to isolate tert-butyl4-(1-(trifluoromethyl)cyclopropyl)phenylcarbamate. It was treated with1:1 DCM/TFA (10 mL/10 mL) at RT for 10 min, concentrated in vacuo, takeninto chloroform, washed with 1N NaOH (aq) and water, dried, concentratedand subjected to silica flash column to isolate4-(1-(trifluoromethyl)cyclopropyl)aniline (330) (300 mg, 40%).

The title compound,5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)-3-(4-(1-(trifluoromethyl)cyclopropyl)phenylamino)pyrazine-2-carboxamide(331), was prepared using the same synthetic scheme illustrated forExample 237 using 4-(1-(trifluoromethyl)cyclopropyl)aniline (330). LC-MS(ESI): m/z (M+1) 506.5. UV: λ=269, 279, 307, 334, 372 nm. Proton NMR(CD₃OD): δ 7.64 (1H, s), 7.63 (2H, d, J=8.5 Hz), 7.39 (2H, d, J=8.5 Hz),5.05 (1H, m), 4.29 (1H, m), 3.88 (1H, m), 3.06 (1H, m), 2.96 (6H, s),1.89 (2H, m), 1.74 (1H, m), 1.67 (1H, m), 1.31 (2H, m), 1.16 (3H, d,J=7.0 Hz), 1.04 (2H, m) ppm.

Example 240: Synthesis of3-(4-(1-cyanocyclopropyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

The title compound,3-(4-(1-cyanocyclopropyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(332), was prepared by the same synthetic scheme illustrated for Example237 using 1-(4-aminophenyl)cyclopropanecarbonitrile. LC-MS (ESI): m/z(M+1) 463.4. UV: λ=270, 280, 308, 336, 372 nm. Proton NMR (CD₃OD): δ7.66 (2H, d, J=8.5 Hz), 7.64 (1H, s), 7.27 (2H, d, J=8.5 Hz), 5.08 (1H,m), 4.27 (1H, m), 3.88 (1H, m), 3.07 (1H, m), 2.97 (6H, s), 1.90 (2H,m), 1.76 (1H, m), 1.67 (3H, m), 1.43 (2H, m), 1.16 (3H, d, J=7.0 Hz)ppm. Compound 333,3-(4-(1-carbamoylcyclopropyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide,was also found and isolated as a major by-product in the final step.

Example 241: Synthesis of3-(4-(1-carbamoylcyclopropyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

The title compound,3-(4-(1-carbamoylcyclopropyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(333), was found and isolated as a major by-product in the final stepduring the preparation of3-(4-(1-cyanocyclopropyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(332). LC-MS (ESI): m/z (M+1) 481.3. UV: λ=270, 279, 307, 336, 372 nm.Proton NMR (CD₃OD): δ 7.67 (2H, d, J=8.5 Hz), 7.64 (1H, s), 7.36 (2H, d,J=8.5 Hz), 5.08 (1H, m), 4.27 (1H, m), 3.87 (1H, m), 3.07 (1H, m), 2.96(6H, s), 1.90 (1H, m), 1.86 (1H, m), 1.75 (1H, m), 1.66 (1H, m), 1.48(2H, m), 1.16 (3H, d, J=7.0 Hz), 1.06 (2H, m) ppm.

Example 242: Synthesis of5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carboxamide

The title compound,5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carboxamide(334), was prepared by the same synthetic scheme illustrated for Example237 using 5-amino-3-methylisothiazole hydrochloride. LC-MS (ESI): m/z(M+1) 419.5. UV: λ=279, 287, 315, 343, 368 nm. Proton NMR (CD₃OD): δ7.88 (1H, s), 6.89 (1H, s), 5.05 (1H, m), 4.44 (1H, m), 3.91 (1H, m),3.22 (1H, m), 2.95 (6H, s), 2.47 (3H, s), 1.99-1.90 (2H, m), 1.80-1.72(2H, m), 1.27 (3H, d, J=7.0 Hz) ppm.

Example 243: Synthesis of5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)-3-(4-isopropoxyphenylamino)pyrazine-2-carboxamide

The title compound,5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)-3-(4-isopropoxyphenylamino)pyrazine-2-carboxamide(335), was prepared by the same synthetic scheme illustrated for Example237 using 4-isopropoxyaniline. LC-MS (ESI): m/z (M+1) 456.3. UV: λ=269,275, 304, 339, 373 nm. Proton NMR (CD₃OD): δ 7.58 (1H, s), 7.49 (2H, d,J=9.0 Hz), 6.85 (2H, d, J=9.0 Hz), 4.97 (1H, m), 4.52 (1H, m), 4.30 (1H,m), 3.86 (1H, m), 3.01 (1H, m), 2.95 (6H, s), 1.87 (2H, m), 1.72 (1H,m), 1.63 (1H, m), 1.30 (6H, d, J=6.5 Hz), 1.14 (3H, d, J=7.0 Hz) ppm.

Example 244: Synthesis of5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)-3-(4-(methylsulfonyl)phenylamino)pyrazine-2-carboxamide

The title compound,5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)-3-(4-(methylsulfonyl)phenylamino)pyrazine-2-carboxamide(336), was prepared by the same synthetic scheme illustrated for Example237 using 4-methylsulfonylaniline. LC-MS (ESI): m/z (M+1) 476.2. UV:λ=280, 293, 319, 346, 367 nm.

Example 245: Synthesis of3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

The mixture of3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea(326) (300 mg, 0.93 mmol), tert-butyl4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (325 mg, 1.12mmol), fine-powder cesium carbonate (1300 mg, 4.00 mmol), Pd(OAc)₂ (67mg, 0.30 mmol), BINAP (190 mg, 0.30 mmol) in 45 mL dioxane was degassedwith nitrogen stream for 3 min. It was then stirred in 115° C. bath innitrogen atmosphere for 3 hours. The mixture was cooled to RT, dilutedwith 150 mL EtOAc, and filtered using ChemGlass OP-6602-12 disposablefunnel. The filtrate was concentrated in vacuo and subjected to silicaflash column using 0 to 5% MeOH in DCM to isolate tert-butyl4-(4-(3-cyano-6-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate(337). It was dissolved in 20 mL MeOH and 4 mL DMSO. To it were addedone NaOH solid bead (about 100 mg) and then 1 mL 30% H₂O₂. The mixturewas stirred at RT for 1 hour, diluted with 10 mL MeCN, stirred for 5min, and concentrated on rotavap. The residue was diluted with 150 mLEtOAc, washed with water (×2), dried, and subjected to silica flashcolumn using 0 to 5% MeOH in DCM to isolate tert-butyl4-(4-(3-carbamoyl-6-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate(338). It was treated with 2:1 DCM and TFA (10 mL/5 mL) at RT for 30 minand concentrated to dryness to give crude5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(339) as TFA salt. Half of this salt was dissolved in 10 mL1,2-dichloroethane (DCE) and 2 mL NMP. To it were added DIEA (700 μL,4.0 mmol) and cyclopentanone (1.06 mL, 12.0 mmol). The mixture wasstirred at RT for 2 hours. To it were then added acetic acid (450 μL,8.0 mmol) and then NaBH(OAc)₃ (510 mg, 2.4 mmol). The mixture wasstirred at RT for overnight, diluted with 20 mL MeOH, concentrated invacuo, acidified with TFA (1 mL). and directly subjected to reversephase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases toisolate3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(340) as HCl salt (142 mg, 54% overall yield for 4 steps). LC-MS (ESI):m/z (M+1) 564.0. UV: λ=268, 278, 306, 336, 372 nm.

Proton NMR (CD₃OD): δ 7.73-7.63 (3H, m), 7.34 (2H, m), 5.05 (1H, m),4.33 (1H, m), 3.87 (1H, m), 3.64-3.50 (2H, m), 3.06 (1H, m), 2.96 (6H,s), 2.89-2.63 (3H, m), 2.23-2.09 (4H, m), 2.01-1.91 (4H, m), 1.89-1.62(8H, m), 1.41-1.27 (3H, s), 1.17 (3H, d, J=7.0 Hz) ppm.

Example 246: Synthesis of3-(4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

The title compound,3-(4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(341), was prepared by the same synthetic scheme illustrated for Example245 using cyclobutanone. LC-MS (ESI): m/z (M+1) 549.9. UV: λ=268, 278,306, 336, 372 nm. Proton NMR (CD₃OD): δ 7.72-7.64 (3H, m), 7.34 (2H, m),5.06 (1H, m), 4.33 (1H, m), 3.88 (1H, m), 3.51-3.35 (2H, m), 3.12-3.04(1H, m), 2.95 (6H, s), 2.70-2.61 (3H, m), 2.40-2.11 (6H, m), 1.93-1.64(8H, m), 1.40-1.27 (3H, s), 1.17 (3H, d, J=6.5 Hz) ppm.

Example 247: Synthesis of3-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

To a solution of 4-(4-bromophenyl)-4-methylpiperidine (285) (10.5 g,41.3 mmol), (1-ethoxycyclopropoxy)trimethylsilane (18.0 g, 103.6 mmol)and NaBH₃CN (12.46 g, 198.1 mmol) in MeOH (100 mL) was added acetic acid(0.5 mL). The resulting mixture was stirred at 90° C. under N₂atmosphere for 2 hours. After the reaction was cooled down to RT, thesolvent was removed in vacuo, and the residue was partitioned in aqueousNaHCO₃(200 mL) and DCM (200 mL). The layers was separated, the aqueouswas extracted with DCM (50 mL×3). The combined organic layers werewashed with brine, dried, concentrated and subjected to silica flashcolumn chromatography using 0 to 5% EtOAc in PE to afford4-(4-bromophenyl)-1-cyclopropyl-4-methylpiperidine (341) (8 g, 66%) asan oil.

To a suspended of 4-(4-bromophenyl)-1-cyclopropyl-4-methylpiperidine(341) (16.0 g, 54.5 mmol), (dicyclohexylphosphino)biphenyl (1.9 g, 5.4mmol) and Pd₂(dba)₃ (2.5 g, 27.2 mmol) in anhydrous THF (100 mL) wasadded LiHMDS (1M, 109 mL, 109 mmol). The resulting mixture was purgedwith N₂ and then stirred at 60° C. for overnight under N₂ atmosphere.After cooled down to RT, the mixture was diluted with water (100 mL) andextracted with DCM (50 mL×3). The combined organic layers were washedwith brine, dried, concentrated and subjected to silica flash columnchromatography using 0 to 50% EtOAc in PE to give4-(1-cyclopropyl-4-methylpiperidin-4-yl)aniline (342) (5 g, 40%) as awhite solid. Proton NMR (CDCl₃): δ 7.16 (2H, d, J=8.5 Hz), 6.69 (2H, d,J=8.6 Hz), 3.58 (2H, s), 2.82-2.65 (2H, m), 2.64-2.49 (2H, m), 2.14-2.04(2H, m), 1.77-1.65 (2H, m), 1.21 (3H, s), 0.96-0.82 (1H, m), 0.56-0.28(4H, m) ppm.

The mixture of3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea(326) (75 mg, 0.23 mmol),4-(1-cyclopropyl-4-methylpiperidin-4-yl)aniline (342) (65 mg, 0.28mmol), fine-powder cesium carbonate (230 mg, 0.70 mmol), Pd(OAc)₂ (16mg, 0.07 mmol), BINAP (44 mg, 0.07 mmol) in 20 mL dioxane was degassedwith nitrogen stream for 3 min. It was then stirred in 115° C. bath innitrogen atmosphere for 2 hours. The mixture was cooled to RT, dilutedwith 100 mL EtOAc, and filtered using ChemGlass OP-6602-12 disposablefunnel. The filtrate was concentrated in vacuo and subjected to silicaflash column using 0 to 10% MeOH in DCM to isolate3-((2R,3R)-1-(5-cyano-6-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea(343). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were addedfine-powder cesium carbonate (50 mg), DIEA (60 μL), and then 0.5 mL 30%H₂O₂. The mixture was stirred at RT for 30 min, diluted with 10 mL MeCN,stirred for 5 min, and concentrated on rotavap. The residue wasacidified with TFA (0.5 mL) and directly subjected to reverse phase prepHPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate3-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(344) as HCl salt (68 mg, 55% overall yield for 2 steps). LC-MS (ESI):m/z (M+1) 535.9. UV: λ=268, 278, 306, 336, 372 nm. Proton NMR (CD₃OD): δ7.74-7.64 (3H, m), 7.38-7.33 (2H, m), 5.08 (1H, m), 4.33 (1H, m), 3.88(1H, m), 3.62-3.47 (2H, m), 3.05 (2H, m), 2.96 (6H, s), 2.70-2.64 (2H,m), 2.20-2.12 (2H, m), 1.91-1.86 (4H, m), 1.75 (1H, m), 1.66 (1H, m),1.45-1.26 (3H, s), 1.17 (3H, d, J=7.0 Hz), 1.02-0.89 (4H, m) ppm.

Example 248: Synthesis of3-(4-(1-cyanocyclopentyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

The title compound,3-(4-(1-cyanocyclopentyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(345), was prepared by the same synthetic scheme illustrated for Example247 using 1-(4-aminophenyl)cyclopentanecarbonitrile. LC-MS (ESI): m/z(M+1) 491.6. UV: λ=269, 279, 307, 335, 372 nm. Proton NMR (CD₃OD): δ7.69 (2H, d, J=8.5 Hz), 7.64 (1H, s), 7.42 (2H, d, J=8.5 Hz), 5.08 (1H,m), 4.28 (1H, m), 3.88 (1H, m), 3.07 (1H, m), 2.96 (6H, s), 2.42 (2H,m), 2.12 (2H, m), 1.99 (4H, m), 1.90 (2H, m), 1.73 (1H, m), 1.66 (1H,m), 1.16 (3H, d, J=7.0 Hz) ppm. Compound 346,3-(4-(1-carbamoylcyclopentyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide,was also found and isolated as a major by-product in the final step.

Example 249: Synthesis of3-(4-(1-carbamoylcyclopentyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

The title compound,3-(4-(1-carbamoylcyclopentyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(346), was found and isolated as a major by-product in the final stepduring the preparation of3-(4-(1-cyanocyclopentyl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(345). LC-MS (ESI): m/z (M+1) 509.5. UV: λ=270, 278, 307, 336, 372 nm.

Example 250: Synthesis of3-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(54)

The mixture of 4-(4-bromophenyl)piperidine-4-carbonitrile (347, 520 mg,1.96 mmol), tert-butyl carbamate (460 mg, 3.92 mmol), Pd₂(dba)₃ (180 mg,0.20 mmol), XantPhos (350 mg, 0.60 mmol), fine-powder Cs₂CO₃ (1.96 g,6.0 mmol) in 30 mL dioxane was degassed using N₂ stream for 5 min andstirred in 115° C. bath in N₂ atmosphere for overnight. It was cooled toRT, diluted with EtOAc 200 mL and filtered. The filtrate wasconcentrated in vacuo and subjected to silica flash column using 0 to30% MeOH in DCM to afford tert-butyl4-(4-cyanopiperidin-4-yl)phenylcarbamate (348, 230 mg, 39%).

Compound 348 (230 mg, 0.77 mmol) was dissolved in 20 mL MeOH and 1 mLHOAc. To the solution was added cyclopentanone (280 μL, 3.08 mmol) andthe mixture was stirred at RT for 2.5 hours. Then NaBH₃CN (290 mg, 4.62mmol) was added, and the mixture was stirred at RT for overnight. It wasconcentrated in vacuo, diluted with EtOAc 150 mL, washed with 1N NaOHand water, dried, concentrated in vacuo to dryness to give crudetert-butyl 4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylcarbamate (349,280 mg, 98%). It was treated with 4N HCl in dioxane at RT for 4 hoursand concentrated in vacuo to dryness to give4-(4-aminophenyl)-1-cyclopentylpiperidine-4-carbonitrile hydrochloride(350, 250 mg, quantitative yield).

The mixture of3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea(326) (100 mg, 0.31 mmol),4-(4-aminophenyl)-1-cyclopentylpiperidine-4-carbonitrile hydrochloride(350) (114 mg, 0.37 mmol), fine-powder cesium carbonate (400 mg, 1.24mmol), Pd(OAc)₂ (22 mg, 0.1 mmol), BINAP (62 mg, 0.1 mmol) in 20 mLdioxane was degassed with nitrogen stream for 3 min. It was then stirredin 115° C. bath in nitrogen atmosphere for 2.5 hours. The mixture wascooled to RT, diluted with 100 mL EtOAc, and filtered. The filtrate wasconcentrated in vacuo and subjected to silica flash column using 0 to10% MeOH in chloroform to isolate3-((2R,3R)-1-(5-cyano-6-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea(351). It was dissolved in 10 mL MeOH and 1 mL DMSO. To it were addedone NaOH solid bead (about 100 mg), DIEA (60 μL), and then 1 mL 30%H₂O₂. The mixture was stirred at RT for 1 hour, diluted with 10 mL MeCN,stirred for 5 min, and concentrated on rotavap. The residue wasacidified with TFA (0.5 mL) and directly subjected to reverse phase prepHPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate3-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(352) as HCl salt (22 mg). LC-MS (ESI): m/z (M+1) 574.6. UV: λ=270, 281,309, 336, 371 nm. Proton NMR (CD₃OD): δ 7.78 (2H, d, J=9.0 Hz), 7.67(1H, s), 7.49 (2H, d, J=8.5 Hz), 5.09 (1H, m), 4.28 (1H, m), 3.88 (3H,m), 3.69 (1H, m), 3.36 (2H, m), 3.09 (1H, m), 2.97 (6H, s), 2.51 (2H,m), 2.40 (2H, m), 2.26 (2H, m), 1.89 (4H, m), 1.86-1.66 (6H, m), 1.17(3H, d, J=6.5 Hz) ppm. Compound 353,3-(4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide,was also found and isolated as a major by-product in the final step.

Example 251: Synthesis of3-(4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

The title compound,3-(4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(353, 15 mg), was found and isolated as HCl salt as a major by-productin the final step during the preparation of3-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(352). LC-MS (ESI): m/z (M+1) 592.7. UV: λ=271, 281, 309, 337, 372 nm.Proton NMR (CD₃OD): δ 7.82-7.71 (2H, d, J=8.5 Hz), 7.65 (1H, s),7.46-7.35 (2H, d, J=8.5 Hz), 5.06 (1H, m), 4.30 (1H, m), 3.88 (1H, m),3.69 (1H, m), 3.56 (1H, m), 3.20 (1H, m), 3.08 (1H, m), 2.96 (6H, s),2.83 (2H, m), 2.39-2.22 (2H, m), 2.04 (2H, m), 1.87 (4H, m), 1.76-1.63(6H, m), 1.17 (3H, d, J=6.5 Hz) ppm.

Example 252: Synthesis of5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

(2R,3R)-Benzyl 3-amino-2-methylpiperidine-1-carboxylate (323, 610 mg,2.46 mmol) was dissolved in 10 mL dry THF. To it was added 2-chloroethylisocyante (210 μL, 2.46 mmol), and the mixture was stirred at RT for 2hours. To it was added NaH (60% in mineral oil, 120 mg, 2.95 mmol) andthe mixture was stirred for overnight. Another batch of NaH (120 mg,2.95 mmol) was then added to drive the cyclization to completion inovernight. The mixture was diluted with 150 mL EtOAc and 50 mL water.The organic phase was separated, washed with water, dried, concentratedin vacuo, and subjected to silica flash column using 0 to 4% MeOH in DCMto isolate (2R,3R)-benzyl2-methyl-3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (354, 490mg, 63%) as a white solid.

Compound 354 (490 mg, 1.55 mmol) was dissolved in 15 mL dry THF. It wastreated with NaH (60% in mineral oil, 125 mg, 3.1 mmol) for 15 min atRT. To the mixture was then added iodomethane (200 μL, 3.1 mmol). Themixture was stirred at RT for 1.5 hour, diluted with 150 mL EtOAc and 50water. The organic phase was separated, washed with water, dried,concentrated, and subjected to silica flash column using 0 to 4% MeOH inDCM to isolate (2R,3R)-benzyl2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate(355, 470 mg, 92%). It was dissolved in 100 mL iPrOH. To it was added10% Pd/C (0.5 g), and the mixture was hydrogenated at 40 psi on a Parrshaker for overnight. The mixture was filtered through celite andconcentrated in vacuo to give1-methyl-3-((2R,3R)-2-methylpiperidin-3-yl)imidazolidin-2-one (356) as awhite solid in quantitative yield.

Compound 356 from above was dissolved in 10 mL DMF. To it were added3,5-dichloropyrazine-2-carbonitrile (250 mg, 1.42 mmol) and DIEA (500μL, 2.84 mmol). The mixture was stirred at RT for 2 hours, diluted with150 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, andsubjected to silica flash column using 0 to 3% MeOH in DCM to isolate3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile(357, 200 mg, 42% yield).

The mixture of3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile(357) (100 mg, 0.60 mmol), tert-butyl4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (175 mg, 0.60mmol), fine-powder cesium carbonate (590 mg, 1.80 mmol), Pd(OAc)₂ (45mg, 0.2 mmol), BINAP (125 mg, 0.2 mmol) in 30 mL dioxane was degassedwith nitrogen stream for 3 min. It was then stirred in 115° C. bath innitrogen atmosphere for 70 min. The mixture was cooled to RT, dilutedwith 120 mL EtOAc, and filtered. The filtrate was concentrated in vacuoand subjected to silica flash column using 0 to 4% MeOH in chloroform toisolate tert-butyl4-(4-(3-cyano-6-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate(358). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were addedfine-powder Cs₂CO₃ (50 mg) and then 1 mL 30% H₂O₂. The mixture wasstirred at RT for 30 min, diluted with 10 mL MeCN, stirred for 5 min,and concentrated on rotavap. The residue was diluted with 150 mL EtOAc,washed with water ×3, dried, concentrated in vacuo, and subjected tosilica flash column using 0 to 4% MeOH in DCM to isolate tert-butyl4-(4-(3-carbamoyl-6-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate(359). It was treated with 2:1 DCM/TFA (12 mL/6 mL) at RT for 30 min.The mixture was concentrated in vacuo. One third of the residue wasdissolved in MeOH/water and directly subjected to reverse phase prepHPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(360) as HCl salt (65 mg). LC-MS (ESI): m/z (M+1) 507.8. UV: λ=268, 277,306, 336, 372 nm. Proton NMR (CD₃OD): δ 7.68 (2H, d, J=9.0 Hz), 7.62(1H, s), 7.35 (2H, d, J=8.5 Hz), 5.11 (1H, m), 4.28 (1H, m), 3.89 (1H,m), 3.53 (2H, m), 3.38 (2H, m), 3.30 (2H, m), 3.06 (3H, m), 2.81 (3H,s), 2.42 (2H, m), 2.03 (1H, m), 1.95 (3H, m), 1.83 (1H, m), 1.68 (1H,m), 1.31 (3H, s), 1.21 (3H, d, J=7.0 Hz) ppm.

Example 253: Synthesis of3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

A crude TFA salt of5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(360) (0.2 mmol) was dissolved in 10 mL DCE and 2 mL NMP. To it wereadded DIEA (350 μL, 2.0 mmol) and cyclopentanone (530 μL, 6.0 mmol). Themixture was stirred at RT for 2.5 hours. To it were then added HOAc (230μL, 4.0 mmol) and NaBH(OAc)₃ (260 mg, 1.2 mmol). The mixture was stirredat RT for 1.5 hour, diluted with 10 mL MeOH, stirred, concentrated invacuo, acidified with 0.6 mL TFA, and directly subjected to reversephase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases toisolate3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(361) as HCl salt (80 mg). LC-MS (ESI): m/z (M+1) 575.9. UV: λ=268, 277,306, 336, 372 nm. Proton NMR (CD₃OD): δ 7.72-7.62 (3H, m), 7.35 (2H, m),5.12 (1H, m), 4.29 (1H, m), 3.89 (1H, m), 3.65-3.45 (4H, m), 3.40-3.37(2H, m), 3.09 (1H, m), 2.88 (1H, m), 2.81 (3H, s), 2.65 (2H, m),2.23-1.62 (16H, m), 1.42-1.27 (3H, s), 1.21 (3H, d, J=7.0 Hz) ppm.

Example 254: Synthesis of3-(4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,3-(4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(362), was prepared by the same synthetic scheme illustrated for Example20 using cyclobutanone. LC-MS (ESI): m/z (M+1) 575.9. UV: λ=268, 277,306, 336, 372 nm.

Example 255: Synthesis of3-(4-(4-methyl-1-propionylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

5-((2R,3R)-2-Methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamidehydrochloride (360) (50 mg, 0.092 mmol) was dissolved in 3 mL NMP. To itwere added DIEA (160 μL, 0.92 mmol) and propionyl chloride (32 μL, 0.36mmol). The mixture was stirred at RT for 20 min, quenched with 0.5 mLTFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl(aq) and neat MeCN as mobile phases to isolate3-(4-(4-methyl-1-propionylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(363) as HCl salt (46 mg). LC-MS (ESI): m/z (M+1) 563.7. UV: λ=268, 277,305, 335, 372 nm. Proton NMR (CD₃OD): δ 7.62 (2H, d, J=9.0 Hz), 7.61(1H, s), 7.34 (2H, d, J=9.0 Hz), 5.10 (1H, m), 4.28 (1H, m), 3.89 (1H,m), 3.80 (1H, m), 3.62 (1H, m), 3.51 (2H, m), 3.45-3.35 (4H, m), 3.08(1H, m), 2.81 (3H, d, J=4.0 Hz), 2.41 (2H, m), 2.15 (2H, m), 2.05-1.65(6H, m), 1.28 (3H, s), 1.20 (3H, t, J=7.0 Hz), 1.11 (3H, t, J=7.5 Hz)ppm.

Example 256: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (50 g,250 mmol) and Et₃N (50.5 g, 500 mmol) in DCM (500 mL) was added2-chloroethyl isocyanate (31.65 g, 300 mmol) dropwise. The resultingmixture was stirred at RT for 4 hours before being quenched with water(100 mL). The layers were separated and the organic layer was washedwith brine, dried, concentrated, and subjected to silica flash columnusing 0 to 50% EA in to isolate (R)-tert-butyl3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364) (63.6 g,81.5%) as a colorless oil. At 0° C., to a solution of (R)-tert-butyl3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364, 31.0 g, 102mmol) in anhydrous THF (350 mL) was added NaH (60% in mineral oil, 4.82g, 122 mmol) in small portions slowly. The resulting mixture was stirredat RT for 6 hours before being quenched with water (50 mL). The layerswere separated and the aqueous was extracted with DCM (20 mL×3). Thecombined organic layers were washed with brine, dried, concentrated andsubjected to silica flash column using 0 to 5% MeOH in DCM to isolate(R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365)(25.4 g, 93%) as a white solid. At 0° C., to a solution of(R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365)(16.2 g, 60.2 mmol) in anhydrous THF (160 mL) was added NaH (60%, 3.6 g,90.3 mmol) in small portions. The resulting mixture was stirred at RTfor 30 min, cooled back to 0° C., and then iodomethane (12.9 g, 90.3mmol) was added dropwise. After the addition, the mixture was stirred atRT for 3 hours. The reaction was quenched with water and extracted withDCM (50 mL×2). The combined organic layers were washed with brined,dried, concentrated, and purified by silica flash column using 0 to 3%MeOH in DCM to get (R)-tert-butyl3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (13.0g, 74%) as a light yellow oil. (R)-tert-butyl3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (3.5g, 12.37 mmol) was treated with 40 mL commercial 4N HCl in dioxanedioxane at RT for 2 hours. The solvent was removed in vacuo, and theresidue was basified to pH 9 with ammonium hydroxide. The solvent wasthen removed in vacuo, and the residue was subjected to silica flashcolumn using 0 to 10% MeOH in DCM to isolate(R)-1-methyl-3-(piperidin-3-yl)imidazolidin-2-one (367) (1.2 g, 53%) asan oil. LC-MS (ESI): m/z (M+1) 184.2. Proton NMR (CDCl₃): δ 3.95-3.83(2H, m), 3.75 (1H, s), 3.39-3.26 (5H, m), 3.08-2.97 (1H, m), 2.93-2.79(1H, m), 2.78 (3H, s), 1.94-1.86 (2H, m), 1.82-1.56 (2H, m), 1.48-1.21(1H, m) ppm.

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(370), was prepared by the same synthetic scheme illustrated for Example252 and Example 253 using(R)-1-methyl-3-(piperidin-3-yl)imidazolidin-2-one (367) viaintermediates(R)-3-chloro-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile(368) and(R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(369). LC-MS (ESI): m/z (M+1) 547.5. UV: λ=268, 276, 305, 336, 373 nm.Proton NMR (CD₃OD): δ 7.65 (1H, s), 7.59 (2H, d, J=8.5 Hz), 7.20 (2H, d,J=8.5 Hz), 4.41-4.36 (2H, m), 3.78-3.71 (3H, m), 3.56 (1H, m), 3.50-3.42(2H, m), 3.38-3.31 (2H, m), 3.19-3.11 (3H, m), 3.03 (1H, m), 2.87 (1H,m), 2.81 (3H, s), 2.22 (2H, m), 2.15 (2H, m), 1.96-1.84 (7H, m),1.77-1.67 (5H, m) ppm.

Example 257: Synthesis of(R)-3-(4-(1-ethylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-ethylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(371), was prepared by the same synthetic scheme illustrated for Example256 using aldehyde. LC-MS (ESI): m/z (M+1) 507.4. UV: λ=268, 276, 305,336, 372 nm.

Example 258: Synthesis of(R)-3-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(372), was prepared by the same synthetic scheme illustrated for Example256 using cyclobutanone. LC-MS (ESI): m/z (M+1) 533.8. UV: λ=268, 276,305, 335, 372 nm. Proton NMR (CD₃OD): δ 7.63 (1H, s), 7.58 (2H, d, J=8.5Hz), 7.19 (2H, d, J=8.5 Hz), 4.40-4.34 (2H, m), 3.76 (1H, m), 3.68 (1H,m), 3.59 (1H, s), 3.56 (1H, s), 3.47 (1H, m), 3.42 (1H, m), 3.36 (2H,m), 3.14 (1H, m), 3.01 (1H, m), 2.92-2.87 (2H, m), 2.81 (3H, s), 2.37(2H, m), 2.32 (2H, m), 2.12 (2H, m), 1.95-1.85 (7H, m), 1.66 (1H, m)ppm.

Example 259: Synthesis of(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(373), was prepared by the same synthetic scheme illustrated for Example256 using 4-(1-cyclopropylpiperidin-4-yl)aniline (322) hydrochloride.LC-MS (ESI): m/z (M+1) 519.2. UV: λ=268, 276, 305, 336, 373 nm. ProtonNMR (CD₃OD): δ 7.64 (1H, s), 7.59 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5Hz), 4.40-4.35 (2H, m), 3.77 (3H, m), 3.48 (1H, m), 3.44 (1H, m), 3.37(2H, m), 3.17 (1H, m), 3.02 (1H, m), 2.92-2.85 (2H, m), 2.80 (3H, s),2.14 (2H, m), 1.95-1.85 (5H, m), 1.66 (1H, m), 1.02 (4H, m) ppm.

Example 260: Synthesis of(R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(1,1-dioxothiomorpholino)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(1,1-dioxothiomorpholino)phenylamino)pyrazine-2-carboxamide(374), was prepared by the same synthetic scheme illustrated for Example256 using 4-(1,1-dioxothiomorpholino)aniline. LC-MS (ESI): m/z (M+1)529.3. UV: λ=309, 348, 374 nm. Proton NMR (CD₃OD): δ 7.60 (1H, s), 7.52(2H, d, J=8.5 Hz), 7.01 (2H, d, J=8.5 Hz), 4.43 (1H, m), 4.33 (1H, m),3.78 (5H, m), 3.47-3.33 (4H, m), 3.17 (4H, m), 3.08 (1H, m), 3.00 (1H,m), 2.81 (3H, s), 1.97-1.83 (3H, m), 1.66 (1H, m) ppm.

Example 261: Synthesis of(R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(phenylamino)pyrazine-2-carboxamide(375), was prepared by the same synthetic scheme illustrated for Example256 using aniline. LC-MS (ESI): m/z (M+1) 396.3. UV: λ=265, 275, 303,333, 372 nm. Proton NMR (CD₃OD): δ 7.63 (1H, s), 7.59 (2H, d, J=7.5 Hz),7.27 (2H, t, J=7.5 Hz), 6.98 (1H, t, J=7.5 Hz), 4.42 (1H, m), 4.36 (1H,m), 3.75 (1H, m), 3.47-3.41 (2H, m), 3.37-3.32 (2H, m), 3.12 (1H, m),3.00 (1H, m), 2.80 (3H, s), 1.95-1.83 (3H, m), 1.67 (1H, m) ppm

Example 262: Synthesis of(R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(1-(trifluoromethyl)cyclopropyl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(1-(trifluoromethyl)cyclopropyl)phenylamino)pyrazine-2-carboxamide(376), was prepared by the same synthetic scheme illustrated for Example256 using 4-(1-(trifluoromethyl)cyclopropyl)aniline (330). LC-MS (ESI):m/z (M+1) 504.5. UV: λ=268, 278, 306, 334, 372 nm. Proton NMR (CD₃OD): δ7.64 (1H, s), 7.60 (2H, d, J=8.5 Hz), 7.38 (2H, d, J=8.5 Hz), 4.47 (1H,m), 4.32 (1H, m), 3.77 (1H, m), 3.48-3.40 (2H, m), 3.47-3.34 (2H, m),3.08 (1H, m), 3.01 (1H, m), 2.82 (3H, s), 1.96-1.82 (3H, m), 1.68 (1H,m), 1.31 (2H, m), 1.05 (2H, m) ppm.

Example 263: Synthesis of(R)-3-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(377), was prepared by the same synthetic scheme illustrated for Example256 using 4-(1-cyclopropyl-4-methylpiperidin-4-yl)aniline (342). LC-MS(ESI): m/z (M+1) 533.7. UV: λ=269, 277, 306, 335, 372 nm.

Example 264: Synthesis of(R)-3-(4-(1-isopropyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-isopropyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(378), was prepared by the same synthetic scheme illustrated for Example256 using tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate(287) and acetone. LC-MS (ESI): m/z (M+1) 535.9. UV: λ=269, 277, 306,336, 372 nm.

Example 265: Synthesis of(R)-3-(4-(4-methyl-1-(oxetan-3-yl)piperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(4-methyl-1-(oxetan-3-yl)piperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(379), was prepared by the same synthetic scheme illustrated for Example256 using tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate(287) and oxetan-3-one. LC-MS (ESI): m/z (M+1) 549.8. UV: λ=269, 277,306, 336, 372 nm. Proton NMR (CD₃OD): δ 7.64 (1H, s), 7.57 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.5 Hz), 4.67 (2H, t, J=7.0 Hz), 4.60 (2H, t, J=6.5Hz), 4.46 (1H, m), 4.34 (1H, m), 3.76 (1H, m), 3.50 (1H, m), 3.47 (1H,m), 3.42 (1H, m), 3.35 (2H, m), 3.08 (1H, m), 3.00 (1H, m), 2.80 (3H,s), 2.32 (2H, m), 2.21 (2H, m), 1.95-1.65 (4H, m), 1.23 (3H, s) ppm.

Example 266: Synthesis of(R)-3-(4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclobutyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(379), was prepared by the same synthetic scheme illustrated for Example256 using tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate(287) and cyclobutanone. LC-MS (ESI): m/z (M+1) 547.9. UV: λ=268, 277,306, 336, 372 nm. Proton NMR (CD₃OD): δ 7.69-7.61 (3H, m), 7.34-7.32(2H, m), 4.48-4.43 (1H, m), 4.38-4.35 (1H, m), 3.79 (1H, m), 3.50-3.35(6H, m), 3.16-3.02 (3H, m), 2.80 (3H, s), 2.67-2.64 (2H, m), 2.42-1.65(14H, m), 1.40-1.27 (3H, s) ppm.

Example 267: Synthesis of(R)-3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(381), was prepared by the same synthetic scheme illustrated for Example256 using tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate(287) and cyclopentanone. LC-MS (ESI): m/z (M+1) 561.9. UV: λ=268, 277,306, 336, 372 nm. Proton NMR (CD₃OD): δ 7.69-7.61 (3H, m), 7.34-7.32(2H, m), 4.47-4.43 (1H, m), 4.38-4.35 (1H, m), 3.79 (1H, m), 3.55-3.35(6H, m), 3.16-2.82 (3H, m), 2.80 (3H, s), 2.66-2.63 (2H, m), 2.25-1.60(16H, m), 1.42-1.27 (3H, s) ppm.

Example 268: Synthesis of(R)-3-(4-(1-formyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-formyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(382), was prepared by the same synthetic scheme illustrated for Example255 using(R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(369), formic acid and PyBOP. LC-MS (ESI): m/z (M+1) 521.5. UV: λ=268,276, 305, 335, 372 nm.

Example 269: Synthesis of(R)-3-(4-(4-methyl-1-propionylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(4-methyl-1-propionylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(383), was prepared by the same synthetic scheme illustrated for Example255 using(R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(369). LC-MS (ESI): m/z (M+1) 549.7. UV: λ=268, 276, 305, 335, 372 nm.Proton NMR (CD₃OD): δ 7.64 (1H, s), 7.59 (2H, d, J=8.5 Hz), 7.32 (2H, d,J=8.5 Hz), 4.48 (1H, m), 4.34 (1H, m), 3.78 (1H, m), 3.63 (1H, m),3.47-3.33 (7H, m), 3.12-2.99 (2H, m), 2.81 (3H, s), 2.41 (2H, m),2.20-2.10 (2H, m), 1.96-1.65 (6H, m), 1.27 (3H, s), 1.11 (3H, t, J=7.5Hz) ppm.

Example 270: Synthesis of(R)-3-(4-(1-(cyclopropanecarbonyl)-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-(cyclopropanecarbonyl)-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(384), was prepared by the same synthetic scheme illustrated for Example255 using (R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide(369) and cyclopropanecarbonyl chloride. LC-MS (ESI): m/z (M+1) 561.7.UV: λ=268, 276, 305, 335, 372 nm. Proton NMR (CD₃OD): δ 7.64 (1H, s),7.59 (2H, d, J=8.5 Hz), 7.33 (2H, d, J=9.0 Hz), 4.48 (1H, m), 4.34 (1H,m), 3.88 (1H, m), 3.78 (2H, m), 3.61 (1H, m), 3.47-3.34 (5H, m),3.12-2.98 (2H, m), 2.81 (3H, s), 2.21 (1H, m), 2.12 (1H, m), 1.97-1.65(6H, m), 1.29 (3H, s), 0.88-0.78 (4H, m) ppm.

Example 271: Synthesis of(R)-3-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(385), was prepared by the same synthetic scheme illustrated for Example256 using 4-(4-aminophenyl)-1-cyclopentylpiperidine-4-carbonitrilehydrochloride (350). LC-MS (ESI): m/z (M+1) 572.8. UV: λ=270, 280, 308,336, 372 nm. Proton NMR (CD₃OD): δ 7.77 (2H, d, J=8.5 Hz), 7.66 (1H, s),7.47 (2H, d, J=8.5 Hz), 4.47 (1H, m), 4.33 (1H, m), 3.88 (1H, s), 3.85(1H, s), 3.76 (1H, m), 3.68 (1H, m), 3.47-3.34 (6H, m), 3.10 (1H, m),3.05 (1H, m), 2.82 (3H, s), 2.52-2.40 (4H, m), 2.25 (2H, m), 1.95-1.65(1 OH, m) ppm. Compound 386,(R)-3-(4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide,was also found and isolated as a major by-product in the final step.

Example 272: Synthesis of(R)-3-(4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(386), was found and isolated as a major by-product in the final stepduring the preparation of(R)-3-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(385). LC-MS (ESI): m/z (M+1) 590.5. UV: λ=271, 280, 309, 337, 372 nm.

Example 273: Synthesis of(R)-3-(4-(4-cyano-1-cyclobutylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(4-cyano-1-cyclobutylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(387), was prepared by the same synthetic scheme illustrated for Example271 using cyclobutanone. LC-MS (ESI): m/z (M+1) 558.8. UV: λ=270, 279,308, 336, 370 nm. Proton NMR (CD₃OD): δ 7.74 (2H, d, J=8.5 Hz), 7.68(1H, s), 7.48 (2H, d, J=9.0 Hz), 4.49 (1H, m), 4.34 (1H, m), 3.86 (1H,m), 3.78 (1H, m), 3.73 (2H, m), 3.49-3.35 (4H, m), 3.20-3.02 (4H, m),2.82 (3H, s), 2.52-2.32 (8H, m), 1.95-1.66 (6H, m) ppm.

Example 274: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(388), was prepared by the same synthetic scheme illustrated for Example256 using (R)-tert-butyl3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) withoutmethylation by iodomethane and sodium hydride. LC-MS (ESI): m/z (M+1)533.8. UV: λ=268, 276, 305, 335, 372 nm. Proton NMR (CD₃OD): δ 7.64 (1H,s), 7.58 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.43 (1H, m), 4.36(1H, m), 3.77 (1H, m), 3.72 (1H, s), 3.70 (1H, s), 3.59-3.52 (3H, m),3.42 (2H, m), 3.13 (3H, m), 3.01 (1H, m), 2.86 (1H, m), 2.21 (2H, m),2.13 (2H, m), 1.97-1.64 (12H, m) ppm.

Example 275: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-ethyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-ethyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(389), was prepared by the same synthetic scheme illustrated for Example256 using iodoethane. LC-MS (ESI): m/z (M+1) 561.8. UV: λ=268, 276, 305,335, 372 nm. Proton NMR (CD₃OD): δ 7.64 (1H, s), 7.59 (2H, d, J=8.5 Hz),7.20 (2H, d, J=9.0 Hz), 4.38 (2H, m), 3.77 (1H, m), 3.73 (1H, s), 3.70(1H, s), 3.51 (1H, m), 3.48 (1H, m), 3.44 (1H, m), 3.38 (2H, m), 3.27(2H, q, J=7.0 Hz), 3.17 (1H, m), 3.14 (2H, m), 3.02 (1H, m), 2.85 (1H,m), 2.22 (2H, m), 2.14 (2H, m), 1.98-1.66 (12H, m), 1.14 (3H, t, J=7.0Hz) ppm.

Example 276: Synthesis of(R)-3-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-ethyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-ethyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (390), wasprepared by the same synthetic scheme illustrated for Example 275 using4-(1-cyclopropyl-4-methylpiperidin-4-yl)aniline (342). LC-MS (ESI): m/z(M+1) 547.5. UV: λ=269, 277, 306, 336, 372 nm. Proton NMR (CD₃OD): δ7.70-7.62 (3H, m), 7.36-7.32 (2H, m), 4.47-4.35 (2H, m), 3.78 (1H, m),3.61-3.37 (6H, m), 3.27 (2H, q, J=7.0 Hz), 3.16-2.99 (3H, m), 2.69-2.62(2H, m), 2.16-1.66 (8H, m), 1.44-1.26 (3H, s), 1.14 (3H, t, J=7.5 Hz),1.02-0.87 (4H, m) ppm.

Example 277: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

To a solution of (R)-tert-butyl3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (10.0 g, 31.17mmol), cyclopropylboronic acid (6.39 g, 74.35 mmol) and pyridine (8.82g, 111.5 mmol) in anhydrous DMF (100 mL) was added Cu(OAc)₂ (6.75 g,37.17 mmol). The resulting mixture was stirred at 40° C. under 02atmosphere (balloon) for 48 hours. After quenched with NH₃.H₂O (10 mL),the mixture was diluted with water (50 mL) and extracted with EtOAc (100mL×3). The organic layers were combined, washed with brine, dried,concentrated, and subjected to silica flash column chromatography using0 to 70% EtOAc in PE to isolate (R)-tert-butyl3-(3-cyclopropyl-2-oxoimidazolidin-1-yl) piperidine-1-carboxylate (391)(2.6 g, 23%) as a light yellow oil.

(R)-tert-Butyl3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (391)(3.0 g, 9.7 mmol) was treated with commercial 4N HCl in dioxane at RT toafford (R)-1-cyclopropyl-3-(piperidin-3-yl)imidazolidin-2-onehydrochloride (392) (2.05 g, 86%) as a light brown solid afterconcentration in vacuo. Proton NMR (DMSO-d₆): δ 9.37 (1H, s), 8.99 (1H,s), 3.89-3.82 (1H, m), 3.64-3.57 (1H, m), 3.28-3.18 (4H, m), 3.11-3.03(1H, m), 2.97-2.87 (1H, m), 2.77-2.67 (1H, m), 2.44-2.29 (1H, m),1.89-1.80 (1H, m), 1.75-1.64 (3H, m), 0.81-0.36 (4H, m) ppm.

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(394), was prepared by the same synthetic scheme illustrated for Example252 using (R)-1-cyclopropyl-3-(piperidin-3-yl)imidazolidin-2-onehydrochloride (392) and 4-(1-cyclopentylpiperidin-4-yl)anilinehydrochloride (304) via intermediates(R)-3-chloro-5-(3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile(393). LC-MS (ESI): m/z (M+1) 573.7. UV: λ=268, 277, 305, 335, 372 nm.

Example 278: Synthesis of(R)-3-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-(3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-(3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(395), was prepared by the same synthetic scheme illustrated for Example277 using 4-(1-cyclobutylpiperidin-4-yl)aniline hydrochloride. LC-MS(ESI): m/z (M+1) 559.9. UV: λ=268, 276, 305, 336, 372 nm. Proton NMR(CD₃OD): δ 7.64 (1H, s), 7.59 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz),4.37 (2H, m), 3.78 (1H, m), 3.71 (1H, m), 3.59 (1H, s), 3.57 (1H, s),3.43 (1H, m), 3.36 (3H, m), 3.15 (1H, m), 3.01 (1H, m), 2.92 (2H, m),2.84 (1H, m), 2.40 (3H, m), 2.29 (2H, m), 2.14 (2H, m), 1.97-1.65 (8H,m), 0.72-0.66 (4H, m) ppm.

Example 279: Synthesis of(R)-5-(3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(396), was prepared by the same synthetic scheme illustrated for Example277 using 4-(1-cyclopropyl-4-methylpiperidin-4-yl)aniline (342). LC-MS(ESI): m/z (M+1) 559.8. UV: λ=268, 277, 306, 336, 372 nm. Proton NMR(CD₃OD): δ 7.71-7.61 (3H, m), 7.38-7.32 (2H, m), 4.45-4.35 (2H, m), 3.79(1H, m), 3.60-3.36 (7H, m), 3.16-2.99 (3H, m), 2.70-2.64 (2H, m), 2.41(1H, m), 2.19-1.66 (7H, m), 1.45-1.26 (3H, s), 1.02-0.87 (4H, m),0.72-0.67 (4H, m) ppm.

Example 280: Synthesis of(R)-5-(3-(3-(3-chlorophenyl)-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

A mixture of 3-chloroaniline (50 g, 0.39 mol) and 1,2-dibromoethane (73g, 0.39 mol) in MeCN (500 mL) was heated at 80° C. for 2 days. Thereaction mixture was concentrated on rotavap and subjected to silicaflash column chromatography using 0 to 30% EtOAc in PE to isolateN-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 10%) as a yellow solid.To a solution of N-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 38.46mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (7.74 g, 38.46mmol) in THF (100 mL) was added DIEA (14.88 g, 115.38 mmol). Theresulting mixture was stirred at 70° C. for 2 days. It was partitionedin EtOAc (50 mL) and water (50 mL). The layers were separated and theaqueous was extracted with EtOAC (50 mL×3). The combined organic layerwas washed with brine, dried, concentrated and subjected to silica flashcolumn chromatography using 0 to 5% MeOH in DCM to isolated(R)-tert-butyl3-(2-(3-chlorophenylamino)ethylamino)piperidine-1-carboxylate (398)(10.1 g, 74.4%) as a white solid.

In ice bath and under N₂ atmosphere, to a stirred solution of(R)-tert-butyl3-(2-(3-chlorophenylamino)ethylamino)piperidine-1-carboxylate (398)(10.1 g, 28.37 mmol) and Et₃N (3.01 g, 29.8 mmol) in anhydrous DCM (300mL) was added a solution of triphosgene (2.95 g, 9.93 mmol) in DCM (100mL) dropwise. The resulting mixture was stirred in ice bath for 1 hour,and quenched with NaHCO₃(aq.) (1M, 50 mL). The mixture was extractedwith DCM (100 mL×3). The combined organic layer was washed with brine,dried, concentrated and subjected to silica flash column chromatographyusing 0 to 5% MeOH in DCM to isolate (R)-tert-butyl3-(3-(3-chlorophenyl)-2-oxoimidazolidin-1-yl) piperidine-1-carboxylate(399) (4 g, 37%) as a white solid. It was treated with 40 mL commercial4N HCl in dioxane to give(R)-1-(3-chlorophenyl)-3-(piperidin-3-yl)imidazolidin-2-onehydrochloride (400) (3.3 g, quant.) as a white solid. Proton NMR(DMSO-d₆): δ 9.26 (1H, s), 8.93 (1H, s), 7.77 (1H, t, J=2.0 Hz),7.47-7.40 (1H, m), 7.35 (1H, t, J=8.1 Hz), 7.06 (1H, dd, J=7.9, 1.1 Hz),4.10-3.94 (1H, m), 3.89-3.76 (2H, m), 3.48 (2H, t, J=8.5 Hz), 3.25-3.14(2H, m), 3.06-2.97 (1H, m), 2.82-2.72 (1H, m), 1.95-1.86 (1H, m),1.83-1.68 (3H, m) ppm.

The title compound,(R)-5-(3-(3-(3-chlorophenyl)-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(402), was prepared by the same synthetic scheme illustrated for Example252 using (R)-1-(3-chlorophenyl)-3-(piperidin-3-yl)imidazolidin-2-onehydrochloride (400) and 4-(1-cyclopentylpiperidin-4-yl)anilinehydrochloride (304) via intermediates(R)-3-chloro-5-(3-(3-(3-chlorophenyl)-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile(401). LC-MS (ESI): m/z (M+1) 644.4. UV: λ=255, 276, 304, 335, 372 nm.

Example 281: Synthesis of3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide

(2R,3R)-Benzyl 3-amino-2-methylpiperidine-1-carboxylate (323, 270 mg,1.09 mmol) was dissolved in 10 mL dry THF. To it was added3-chloropropyl isocyante (112 μL, 1.09 mmol), and the mixture wasstirred at RT for 3 hours. To it was added NaH (60% in mineral oil, 87mg, 2.18 mmol) and the mixture was stirred for overnight. Another batchof NaH (87 mg, 2.18 mmol) was then added to drive the cyclization tocompletion in 4 hours. To the mixture was added iodomethane (540 μL,8.64 mmol), and it was stirred at RT for overnight. It was diluted with120 mL EtOAc and 30 mL water. The organic phase was separated, washedwith water, dried, concentrated and subjected to silica flash columnwith 0 to 4% MeOH in DCM to isolate (2R,3R)-benzyl2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate (403) (350 mg, 93%) as a thick oil. Itwas dissolved in 100 mL MeOH, and with 10% Pd/C (0.5 g) it washydrogenated at 40 psi on a Parr shaker for overnight. The mixture wasfiltered through celite, and the filtrate was concentrated in vacuo toafford1-methyl-3-((2R,3R)-2-methylpiperidin-3-yl)tetrahydropyrimidin-2(1H)-one(404).

1-Methyl-3-((2R,3R)-2-methylpiperidin-3-yl)tetrahydropyrimidin-2(1H)-one(404, 120 mg, 0.55 mmol) was dissolved in 10 mL DMF. To it were added3,5-dichloropyrazine-2-carbonitrile (175 mg, 1.0 mmol) and DIEA (350 μL,2.0 mmol). The mixture was stirred at RT for 30 min, diluted with 150 mLEtOAc, washed with water ×3, dried, concentrated in vacuo, and subjectedto silica flash column using 0 to 3.5% MeOH in DCM to isolate3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile(405, 60 mg, 31% yield).

The mixture of3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile(405) (60 mg, 0.17 mmol), 4-(1-cyclopentylpiperidin-4-yl)anilinehydrochloride (304) (58 mg, 0.21 mmol), fine-powder cesium carbonate(230 mg, 0.68 mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), BINAP (31 mg, 0.05mmol) in 15 mL dioxane was degassed with nitrogen stream for 3 min. Itwas then stirred in 115° C. bath in nitrogen atmosphere for 1 hour. Themixture was cooled to RT, diluted with 100 mL EtOAc, and filtered. Thefiltrate was concentrated in vacuo and subjected to silica flash columnusing 0 to 10% MeOH in chloroform to isolate3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile(406). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were addedone NaOH solid bead (about 100 mg), Et₃N (60 μL), and then 0.5 mL 30%H₂O₂. The mixture was stirred at RT for 30 min, diluted with 10 mL MeCN,stirred for 5 min, and concentrated on rotavap. The residue was dilutedwith 150 mL EtOAc, washed with water ×3, dried, concentrated in vacuo,acidified with 0.2 mL TFA, and directly subjected to reverse phase prepHPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide(407) as HCl salt (58 mg, 59%). LC-MS (ESI): m/z (M+1) 575.8. UV: λ=268,277, 306, 336, 372 nm. Proton NMR (CD₃OD): δ 7.64 (1H, s), 7.61 (2H, d,J=8.5 Hz), 7.20 (2H, d, J=8.5 Hz), 4.93 (1H, m), 4.56-4.30 (3H, m), 3.71(2H, m), 3.55 (1H, m), 3.38 (3H, m), 3.13 (2H, m), 3.06 (1H, m), 2.97(3H, s), 2.84 (1H, m), 2.25-1.65 (18H, m), 1.20 (3H, d, J=6.5 Hz) ppm.

Example 282: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide

(R)-tert-Butyl 3-aminopiperidine-1-carboxylate (1.28 g, 6.4 mmol) wasdissolved in 15 mL dry THF. To it was added 3-chloropropyl isocyante(660 μL, 6.4 mmol), and the mixture was stirred at RT for 3 hours. To itwas added NaH (60% in mineral oil, 310 mg, 7.68 mmol) and the mixturewas stirred for overnight. Another batch of NaH (310 mg, 7.68 mmol) wasthen added to drive the cyclization to completion, The mixture wasdiluted with 200 mL EtOAc, washed with water, dried, concentrated andsubjected to silica flash column using 0 to 5% MeOh in DCM to isolate(R)-tert-butyl3-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate (408)(1.53 g, 84%) as a white solid. It was dissolved in 50 mL dry THF. Tothe solution was added NaH (440 mg, 10.80 mmol), and the mixture wasstirred for 15 min at RT. Then iodomethane (680 μL, 10.80 mmol) wasadded, and it was stirred at RT for overnight. It was diluted with 200mL EtOAc and 30 mL water. The organic phase was separated, washed withwater, dried, concentrated and subjected to silica flash column with 0to 4% MeOH in DCM to isolate (R)-tert-butyl3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate(409) (1.52 g, 95%) as a white solid. It was treated with 20 mLcommercial 4N HCl in dioxane at RT for 30 min to yield(R)-1-methyl-3-(piperidin-3-yl)tetrahydropyrimidin-2(1H)-onehydrochloride (410) (1.27 g) as a white solid after evaporation in vacuoto dryness.

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide(412), was prepared by the same synthetic scheme illustrated for Example281 using (R)-1-methyl-3-(piperidin-3-yl)tetrahydropyrimidin-2(1H)-onehydrochloride (410) and 4-(1-cyclopentylpiperidin-4-yl)anilinehydrochloride (304) via intermediates(R)-3-chloro-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile(411). LC-MS (ESI): m/z (M+1) 561.9. UV: λ=268, 277, 305, 336, 372 nm.Proton NMR (CD₃OD): δ 7.64 (1H, s), 7.59 (2H, d, J=8.5 Hz), 7.18 (2H, d,J=8.5 Hz), 4.44 (1H, m), 4.35 (1H, m), 4.26 (1H, m), 3.72 (1H, s), 3.69(1H, s), 3.54 (1H, m), 3.40-3.32 (4H, m), 3.14-3.06 (3H, m), 2.96 (3H,s), 2.92-2.82 (2H, m), 2.20 (2H, m), 2.12 (2H, m), 2.00-1.65 (14H, m)ppm.

Example 283: Synthesis of(R)-3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide(413), was prepared by the same synthetic scheme illustrated for Example282 using(R)-3-chloro-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile(411) and 4-(1-cyclopentyl-4-methylpiperidin-4-yl)aniline hydrochloride.LC-MS (ESI): m/z (M+1) 575.9. UV: λ=269, 277, 306, 336, 372 nm. ProtonNMR (CD₃OD): δ 7.70-7.61 (3H, m), 7.34-7.31 (2H, m), 4.46 (1H, m), 4.38(1H, m), 4.29 (1H, m), 3.67-3.50 (2H, m), 3.40-3.32 (4H, m), 3.10 (1H,m), 2.96 (3H, s), 2.93-2.82 (3H, m), 2.64 (1H, m), 2.24-1.62 (18H, m),1.42-1.27 (3H, s) ppm.

Example 284: Synthesis of(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide(414), was prepared by the same synthetic scheme illustrated for Example282 using(R)-3-chloro-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile(411) and 4-(1-cyclopropylpiperidin-4-yl)aniline (322) hydrochloride.LC-MS (ESI): m/z (M+1) 533.7. UV: λ=269, 277, 305, 335, 372 nm. ProtonNMR (CD₃OD): δ 7.64 (1H, s), 7.57 (2H, d, J=8.5 Hz), 7.17 (2H, d, J=8.5Hz), 4.43 (1H, m), 4.33 (1H, m), 4.24 (1H, m), 3.76 (1H, s), 3.73 (1H,s), 3.48-3.32 (5H, m), 3.08 (1H, m), 2.95 (3H, s), 2.93-2.81 (3H, m),2.10 (2H, m), 2.03-1.95 (4H, m), 1.90-1.85 (3H, m), 1.65 (1H, m),1.11-0.98 (4H, m) ppm.

Example 285: Synthesis of(R)-3-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide(415), was prepared by the same synthetic scheme illustrated for Example282 using(R)-3-chloro-5-(3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile(411) and 4-(1-cyclopropyl-4-methylpiperidin-4-yl)aniline (342). LC-MS(ESI): m/z (M+1) 547.8. UV: λ=269, 277, 306, 336, 372 nm. Proton NMR(CD₃OD): δ 7.70-7.60 (3H, m), 7.35-7.31 (2H, m), 4.47-4.36 (2H, m), 4.29(1H, m), 3.64-3.47 (3H, m), 3.37-3.32 (3H, m), 3.11-3.05 (2H, m), 2.96(3H, s), 2.93 (1H, m), 2.70-2.62 (2H, m), 2.16 (2H, m), 2.00-1.85 (7H,m), 1.67 (1H, m), 1.44-1.26 (3H, s), 1.03-0.87 (4H, m) ppm.

Example 286: Preparation of3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide

Commercial (3aR,7aR)-tert-butyloctahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (416, CAS:1251010-63-5, 476 mg, 2.1 mmol) was dissolved in 15 mL DMF. To it wereadded 3,5-dichloropyrazine-2-carbonitrile (340 mg, 1.9 mmol) and DIEA(500 μL, 2.9 mmol). The mixture was stirred at RT for 3.5 hours, dilutedwith 100 mL EtOAc, washed with water ×3, dried, concentrated in vacuo,and subjected to silica flash column using 0 to 3% MeOH in DCM toisolate (3aR,7aR)-tert-butyl4-(6-chloro-5-cyanopyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(417, 670 mg, 88%) as a white solid.

The mixture of (3aR,7aR)-tert-butyl4-(6-chloro-5-cyanopyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(417) (400 mg, 1.10 mmol), 4-(1-cyclopentylpiperidin-4-yl)anilinehydrochloride (304) (340 mg, 1.21 mmol), fine-powder cesium carbonate(1.08 g, 3.30 mmol), Pd(OAc)₂ (74 mg, 0.33 mmol), BINAP (206 mg, 0.33mmol) in 40 mL dioxane was degassed with nitrogen stream for 3 min. Itwas then stirred in 115° C. bath in nitrogen atmosphere for 1.5 hour.The mixture was cooled to RT, diluted with 150 mL EtOAc, and filtered.The filtrate was concentrated in vacuo and subjected to silica flashcolumn using 0 to 6% MeOH in DCM to isolate (3aR,7aR)-tert-butyl4-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(418) (480 mg, 76%). It was dissolved in 25 mL MeOH and 2 mL DMSO. To itwere added fine-powder Cs₂CO₃ (100 mg) and then 1 mL 30% H₂O₂. Themixture was stirred at RT for 1 hour, diluted with 10 mL MeCN, stirredfor 5 min, and concentrated on rotavap. The residue was diluted with 150mL EtOAc, washed with water ×2, concentrated in vacuo to give crude(3aR,7aR)-tert-butyl4-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(419). It was treated with 1:1 TFA/DCM at RT for 5 min, concentrated invacuo, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) andneat MeCN as mobile phases to isolate3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide(420) as HCl salt. LC-MS (ESI): m/z (M+1) 490.4. UV: λ=263, 272, 303,334, 370 nm. Proton NMR (CD₃OD): δ 7.68 (1H, s), 7.57 (2H, d, J=8.5 Hz),7.30 (2H, d, J=9.0 Hz), 5.16 (1H, m), 4.21 (1H, m), 3.85 (1H, m), 3.72(2H, d, J=13.0 Hz), 3.58 (2H, m), 3.42 (1H, m), 3.12 (3H, m), 2.89 (1H,m), 2.35 (1H, m), 2.20 (2H, m), 2.14-1.71 (15H, m) ppm.

Example 287: Preparation of(3aR,7aR)-4-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

3-(4-(1-Cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide(420) (82 mg, 0.16 mmol) was dissolved in 3 mL NMP. To it were addedDIEA (290 μL, 1.68 mmol) and then dimethylcarbamoyl chloride (62 μL,0.67 mmol). The mixture was stirred at RT for 2 hours, quenched with 0.5mL TFA, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) andneat MeCN as mobile phases to isolate(3aR,7aR)-4-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide(421) as HCl salt (61 mg, 64%). LC-MS (ESI): m/z (M+1) 561.9. UV: λ=267,275, 304, 334, 372 nm. Proton NMR (CD₃OD): δ 7.64 (1H, m), 7.59 (2H, d,J=7.5 Hz), 7.20 (2H, d, J=8.0 Hz), 4.18 (2H, m), 3.71 (3H, m), 3.61-3.56(2H, m), 3.44 (1H, m), 3.13 (3H, m), 2.90 (7H, s), 2.21 (3H, m), 2.15(2H, m), 2.07 (1H, m), 1.95 (3H, m), 1.87 (3H, m), 1.73 (4H, m), 1.61(2H, m) ppm.

Example 288: Preparation of3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-1-(cyclopropanecarbonyl)dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide

3-(4-(1-Cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide(420) (82 mg, 0.16 mmol) was dissolved in 3 mL NMP. To it were addedDIEA (290 μL, 1.68 mmol) and then cyclopropanecarbonyl chloride (61 μL,0.67 mmol). The mixture was stirred at RT for 2 hours, quenched with 0.5mL TFA, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) andneat MeCN as mobile phases to isolate3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-1-(cyclopropanecarbonyl)dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide(422) as HCl salt (58 mg, 62%). LC-MS (ESI): m/z (M+1) 558.8. UV: λ=266,274, 304, 334, 372 nm.

Example 289: Preparation of(4aR,8aR)-5-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide

Commercial (4aR,8aR)-decahydro-1,5-naphthyridine (423, 120 mg, 0.86mmol) was dissolved in 2 mL NMP. To it were added DIEA (150 μL, 0.86mmol) and then 3,5-dichloropyrazine-2-carbonitrile (150 mg, 0.86 mmol).The mixture was stirred at RT for 1.5 hour, and to it were added DIEA(450 μL, 2.58 mmol) and dimethylcarbamoyl chloride (240 μL, 2.58 mmol).The mixture was stirred at RT for overnight. It was diluted with 100 mLEtOAc, washed with water ×2, dried, concentrated in vacuo, and subjectedto silica flash column using 0 to 3% MeOH in DCM to isolate(4aR,8aR)-5-(6-chloro-5-cyanopyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide(424, 56 mg, 19%). It was mixed with4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (90 mg, 0.32mmol), fine-powder cesium carbonate (210 mg, 0.64 mmol), Pd(OAc)₂ (11mg, 0.05 mmol), BINAP (31 mg, 0.05 mmol) in 15 mL dioxane. The mixturewas degassed with nitrogen stream for 3 min. It was then stirred in 115°C. bath in nitrogen atmosphere for 1.5 hour. The mixture was cooled toRT, diluted with 100 mL EtOAc, and filtered. The filtrate wasconcentrated in vacuo and subjected to silica flash column using 0 to11% MeOH in DCM to isolate(4aR,8aR)-5-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide (425). It was dissolved in 10 mL MeOH and 2 mL DMSO. Toit were added one NaOH solid bead (about 100 mg), Et₃N (60 μL) and then0.5 mL 30% H₂O₂. The mixture was stirred at RT for 30 min, diluted with10 mL MeCN, stirred for 5 min, and concentrated, acidified with 0.3 mLTFA, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) andneat MeCN as mobile phases to isolate(4aR,8aR)-5-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide(426) as HCl salt (23 mg). LC-MS (ESI): m/z (M+1) 575.8. UV: λ=269, 276,305, 335, 372 nm.

Example 290: Synthesis of3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3R,4R)-3-(3,3-dimethylureido)-4-methylpiperidin-1-yl)pyrazine-2-carboxamide

Commercial (3R,4R)-tert-butyl 3-amino-4-methylpiperidine-1-carboxylate(427, 250 mg, 1.16 mmol) was dissolved in 10 mL dry THF. To it wereadded DIEA (610 μL, 3.50 mmol) and dimethylcarbamoyl chloride (214 μL,2.32 mmol). The mixture was stirred at RT for 2 hours, diluted with 100mL EtOAc, washed with water ×3, dried, concentrated, and subjected tosilic flash column using 0 to 5% MeOh in DCM to isolate(3R,4R)-tert-butyl3-(3,3-dimethylureido)-4-methylpiperidine-1-carboxylate (428, 350 mg) inquantitative yield as a white solid. It was treated with 15 mLcommercial 4N HCkl in dioxane at RT for 40 min to yield1,1-dimethyl-3-((3R,4R)-4-methylpiperidin-3-yl)urea hydrochloride (429).

The title compound,3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3R,4R)-3-(3,3-dimethylureido)-4-methylpiperidin-1-yl)pyrazine-2-carboxamide(431), was prepared by the same synthetic scheme illustrated for Example282 using 1,1-dimethyl-3-((3R,4R)-4-methylpiperidin-3-yl)ureahydrochloride (429) and 4-(1-cyclopentylpiperidin-4-yl)anilinehydrochloride (304) via intermediate3-((3R,4R)-1-(6-chloro-5-cyanopyrazin-2-yl)-4-methylpiperidin-3-yl)-1,1-dimethylurea(430). LC-MS (ESI): m/z (M+1) 549.9. UV: λ=268, 278, 306, 336, 373 nm.Proton NMR (CD₃OD): δ 7.61 (1H, s), 7.58 (2H, d, J=8.5 Hz), 7.22 (2H, d,J=8.5 Hz), 4.61 (1H, m), 4.33 (1H, m), 4.07 (1H, m), 3.73 (1H, s), 3.71(1H, s), 3.56 (1H, m), 3.20-3.09 (4H m), 2.87 (1H, m), 2.70 (6H, s),2.23 (2H, m), 2.15 (2H, m), 2.08-1.61 (11H, m), 0.99 (3H, d, J=6.5 Hz)ppm.

Example 291: Synthesis of3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-tetrahydro-1H-pyrrolo[2,3-c]pyridin-6(2H,7H,7aH)-yl)pyrazine-2-carboxamide

The title compound,3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-tetrahydro-1H-pyrrolo[2,3-c]pyridin-6(2H,7H,7aH)-yl)pyrazine-2-carboxamide(433), was prepared by the same synthetic scheme illustrated for Example286 using commercial racemic (3aS,7aR)-tert-butyloctahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (432). LC-MS (ESI):m/z (M+1) 490.4. UV: λ=262, 272, 303, 334, 370 nm. Proton NMR (CD₃OD): δ7.67 (1H, s), 7.59 (2H, d, J=8.5 Hz), 7.28 (2H, d, J=8.5 Hz), 4.50 (1H,dd, J=14.5; 8.0 Hz), 4.12 (1H, dt, J=13.0; 5.0 Hz), 3.87 (1H, m), 3.78(1H, dd, J=15.0; 4.0 Hz), 3.73 (1H, s), 3.71 (1H, s), 3.56 (1H, m),3.45-3.32 (3H, m), 3.14 (2H, m), 2.88 (1H, m), 2.66 (1H, m), 2.29 (1H,m), 2.21 (2H, m), 2.14-1.96 (6H, m), 1.88 (2H, m), 1.81 (2H, m), 1.72(2H, m), 1.62 (1H, m) ppm.

Example 292: Synthesis of(3aS,7aR)-6-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-H-pyrrolo[2,3-c]pyridine-1-carboxamide

The title compound,(3aS,7aR)-6-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxamide(434), was prepared by the same synthetic scheme illustrated for Example287 using racemic3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-tetrahydro-1H-pyrrolo[2,3-c]pyridin-6(2H,7H,7aH)-yl)pyrazine-2-carboxamide(433). LC-MS (ESI): m/z (M+1) 561.9. UV: λ=268, 279, 307, 336, 373 nm.Proton NMR (CD₃OD): δ 7.60 (2H, d, J=8.5 Hz), 7.50 (1H, s), 7.24 (2H, d,J=8.5 Hz), 4.75 (1H, m), 4.35 (1H, m), 3.96 (1H, m), 3.73 (1H, s), 3.70(1H, s), 3.56 (1H, m), 3.43 (1H, m), 3.15-3.12 (4H, m), 2.86 (1H, m),2.53 (7H, s), 2.25-2.14 (4H, m), 1.99-1.87 (6H, m), 1.78-1.72 (5H, m),1.62 (1H, m) ppm.

Example 293: Synthesis of3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aS,7aR)-1-(cyclopropanecarbonyl)tetrahydro-1H-pyrrolo[2,3-c]pyridin-6(2H,7H,7aH)-yl)pyrazine-2-carboxamide

The title compound,3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aS,7aR)-1-(cyclopropanecarbonyl)tetrahydro-1H-pyrrolo[2,3-c]pyridin-6(2H,7H,7aH)-yl)pyrazine-2-carboxamide(435), was prepared by the same synthetic scheme illustrated for Example288 using racemic3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-tetrahydro-1H-pyrrolo[2,3-c]pyridin-6(2H,7H,7aH)-yl)pyrazine-2-carboxamide(433). LC-MS (ESI): m/z (M+1) 558.8. UV: λ=267, 277, 306, 336, 372 nm.

Example 294: Synthesis of(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(436), was prepared by the same synthetic scheme illustrated for(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(206) hydrochloride, shown in Example 165 using4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304). LC-MS (ESI):m/z (M+1) 464.3. UV: λ=263, 273, 304, 335, 372 nm. Proton NMR (CD₃OD): δ7.68 (1H, s), 7.59 (2H, d, J=9.0 Hz), 7.26 (2H, d, J=8.5 Hz), 4.25 (1H,dd, J=13.0; 3.0 Hz), 4.01 (1H, dt, J=9.0; 4.5 Hz), 3.72 (2H, d, J=10.0Hz), 3.58-3.54 (2H, m), 3.45 (2H, m), 3.14 (2H, m), 2.89 (1H, m),2.22-1.71 (16H, m) ppm.

Example 295: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-formamidopiperidin-1-yl)pyrazine-2-carboxamide

(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(436) (50 mg, 0.1 mmol) was dissolved in 4 mL DMF. To it were addedformic acid (20 μL, 0.5 mmol), DIEA (180 μL, 1.0 mmol) and then PyBOP(105 mg, 0.2 mmol). The mixture was stirred at RT for 2 hours, quenchedwith 0.3 mL TFA, and directly subjected to reverse phase preparativeHPLC using 5 mM HCl (aq) and nest MeCN to isolate the title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-formamidopiperidin-1-yl)pyrazine-2-carboxamide(437), as HCl salt (24 mg). LC-MS (ESI): m/z (M+1) 492.7. UV: λ=267,276, 305, 335, 372 nm. Proton NMR (CD₃OD): δ 8.06 (1H, s), 7.65 (1H, s),7.58 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.19 (1H, m), 4.01 (1H,m), 3.93 (1H, m), 3.71 (2H, d, J=12.0 Hz), 3.54 (1H, m), 3.46 (1H, m),3.38 (1H, m), 3.12 (2H, m), 2.86 (1H, m), 2.22-1.66 (16H, m) ppm.

Example 296: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-propionamidopiperidin-1-yl)pyrazine-2-carboxamide

(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(436) (40 mg, 0.075 mmol) was dissolved in 3 mL NMP. To it were addedDIEA (80 μL, 0.45 mmol) and then propionyl chloride (20 μL, 0.23 mmol).The mixture was stirred at RT for 30 min, quenched with 0.3 mL TFA, anddirectly subjected to reverse phase preparative HPLC using 5 mM HCl (aq)and nest MeCN to isolate the title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-propionamidopiperidin-1-yl)pyrazine-2-carboxamide(438), as HCl salt (23 mg). LC-MS (ESI): m/z (M+1) 520.6. UV: λ=267,276, 305, 335, 372 nm. Proton NMR (CD₃OD): δ 7.62 (1H, s), 7.59 (2H, d,J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.19 (1H, m), 4.01 (1H, m), 3.91 (1H,m), 3.72 (2H, d, J=12.0 Hz), 3.55 (1H, m), 3.42 (1H, m), 3.38 (1H, m),3.12 (2H, m), 2.86 (1H, m), 2.22-1.64 (18H, m), 1.12 (3H, t, J=7.5 Hz)ppm.

Example 297: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-ethyl-3-methylureido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3-ethyl-3-methylureido)piperidin-1-yl)pyrazine-2-carboxamide(436), was prepared by the same synthetic scheme illustrated for Example296 using N-ethyl-N-methylcarbamoyl chloride. LC-MS (ESI): m/z (M+1)549.6. UV: λ=268, 277, 306, 336, 373 nm. Proton NMR (CD₃OD): δ 7.65 (1H,s), 7.61 (2H, d, J=9.0 Hz), 7.21 (2H, d, J=8.5 Hz), 4.28 (1H, m), 4.19(1H, m), 3.78 (1H, m), 3.71 (2H, d, J=12.5 Hz), 3.56 (1H, m), 3.44 (1H,m), 3.26-3.16 (3H, m), 3.12 (2H, m), 2.86 (1H, m), 2.84 (3H, s),2.24-1.63 (18H, m), 1.08 (3H, t, J=7.0 Hz) ppm.

Example 298: Synthesis of (R)-ethyl1-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate

The title compound, (R)-ethyl1-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate(440), was prepared by the same synthetic scheme illustrated for Example296 using ethyl chloroformate. LC-MS (ESI): m/z (M+1) 536.8. UV: λ=267,276, 305, 335, 373 nm.

Example 299: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(cyclopropanecarboxamido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(cyclopropanecarboxamido)piperidin-1-yl)pyrazine-2-carboxamide(441), was prepared by the same synthetic scheme illustrated for Example296 using cyclopropanecarbonyl chloride. LC-MS (ESI): m/z (M+1) 532.8.UV: λ=267, 277, 306, 336, 372 nm.

Example 300: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(methylsulfonamido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(methylsulfonamido)piperidin-1-yl)pyrazine-2-carboxamide(442), was prepared by the same synthetic scheme illustrated for Example296 using methanesulfonyl chloride. LC-MS (ESI): m/z (M+1) 542.9. UV:λ=266, 275, 304, 335, 372 nm. Proton NMR (CD₃OD): δ 7.63 (1H, s), 7.60(2H, d, J=9.0 Hz), 7.24 (2H, d, J=8.5 Hz), 4.55 (1H, m), 4.09 (1H, m),3.70 (2H, d, J=12.5 Hz), 3.55 (1H, m), 3.43 (1H, m), 3.20 (1H, m),3.14-3.06 (3H, m), 2.93 (3H, s), 2.86 (1H, m), 2.24-1.61 918H, m) ppm.

Example 301: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(ethylsulfonamido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(ethylsulfonamido)piperidin-1-yl)pyrazine-2-carboxamide(443), was prepared by the same synthetic scheme illustrated for Example296 using ethanesulfonyl chloride. LC-MS (ESI): m/z (M+1) 556.9. UV:λ=266, 276, 305, 335, 372 nm.

Example 302: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(N,N-dimethylsulfamoylamino)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(N,N-dimethylsulfamoylamino)piperidin-1-yl)pyrazine-2-carboxamide(444), was prepared by the same synthetic scheme illustrated for Example296 using dimethylsulfamoyl chloride. LC-MS (ESI): m/z (M+1) 571.8. UV:λ=266, 276, 305, 335, 373 nm.

Example 303: Synthesis of(R)-5-(3-benzamidopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-benzamidopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(445), was prepared by the same synthetic scheme illustrated for Example296 using benzoyl chloride. LC-MS (ESI): m/z (M+1) 568.9. UV: λ=267,276, 305, 335, 372 nm.

Example 304: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(nicotinamido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(nicotinamido)piperidin-1-yl)pyrazine-2-carboxamide(446), was prepared by the same synthetic scheme illustrated for Example295 using nicotinic acid. LC-MS (ESI): m/z (M+1) 569.6. UV: λ=265, 277,305, 336, 373 nm. Proton NMR (CD₃OD): δ 9.13 (1H, s), 8.91 (1H, d, J=5.5Hz), 8.74 (1H, d, J=8.0 Hz), 8.03 (1H, dd, J=8.0; 5.5 Hz), 7.67 (1H, s),7.58 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz), 4.35 (1H, dd, J=13.0;3.5 Hz), 4.17 (1H, m), 4.13 (1H, m), 3.69 (2H, d, J=12.5 Hz), 3.57-3.47(2H, m), 3.42 (1H, m), 3.11 (2H, td, J=12.5; 2.5 Hz), 2.84 (1H, tt,J=12.5; 3.5 Hz), 2.23-1.71 (18H, m) ppm.

Example 305: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(5-fluoronicotinamido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(5-fluoronicotinamido)piperidin-1-yl)pyrazine-2-carboxamide(447), was prepared by the same synthetic scheme illustrated for Example295 using 5-fluoronicotinic acid. LC-MS (ESI): m/z (M+1) 587.9. UV:λ=268, 278, 305, 336, 373 nm. Proton NMR (CD₃OD): δ 8.85 (1H, s), 8.71(1H, d, J=3.0 Hz), 8.08 (1H, m), 7.67 (1H, s), 7.58 (2H, d, J=8.5 Hz),7.18 (2H, d, J=8.5 Hz), 4.39 (1H, dd, J=13.0; 3.5 Hz), 4.16 (1H, m),4.12 (1H, m), 3.69 (2H, d, J=11.5 Hz), 3.54 (1H, m), 3.46-3.37 (2H, m),3.11 (2H, td, J=12.5; 2.5 Hz), 2.82 (1H, tt, J=12.5; 3.5 Hz), 2.25-1.70(18H, m) ppm.

Example 306: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(2-oxopyrrolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(436) (50 mg, 0.1 mmol) was dissolved in 4 mL DMF. To it were added DIEA(180 μL, 1.0 mmol) and then 4-bromobutyryl chloride (56 mg, 0.3 mmol).The mixture was stirred at RT for 1.5 hours, diluted with 60 mL EtOAc,washed with water ×3, dried, concentrated in vacuo to afford crude(R)-5-(3-(4-bromobutanamido)piperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(448). It was dissolved in 3 mL dry DMF and the solution was stirred atRT. To it was added NaH (60%, 30 mg), and the mixture was stirred for 1hour. It was quenched with 0.5 mL TFA, and directly subjected to reversephase preparative HPLC using 5 mM HCl (aq) and nest MeCN to isolate thetitle compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(2-oxopyrrolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide(449), as HCl salt (7 mg). LC-MS (ESI): m/z (M+1) 532.6. UV: λ=267, 275,305, 335, 373 nm.

Example 307: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(1-oxoisoindolin-2-yl)piperidin-1-yl)pyrazine-2-carboxamide

(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(436) (50 mg, 0.1 mmol) was dissolved in 4 mL DMF. To it were added DIEA(180 μL, 1.0 mmol) and then methyl 2-bromomethylbenzoate (46 mg, 0.2mmol) at RT. The reaction temperature was raised to 60° C. and themixture was stirred for overnight. It was cooled to RT, quenched with0.5 mL TFA, and directly subjected to reverse phase preparative HPLCusing 5 mM HCl (aq) and nest MeCN to isolate the title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(1-oxoisoindolin-2-yl)piperidin-1-yl)pyrazine-2-carboxamide(450), as HCl salt (19 mg). LC-MS (ESI): m/z (M+1) 580.8. UV: λ=269,275, 304, 335, 372 nm. Proton NMR (CD₃OD): δ 7.84 (1H, d, J=7.5 Hz),7.69 (1H, s), 7.66-7.58 (2H, m), 7.56-7.52 (3H, m), 7.12 (2H, d, J=8.5Hz), 4.67-4.57 (3H, m), 4.40-4.30 (2H, m), 3.64 (2H, m), 3.55 (1H, m),3.27-3.06 (4H, m), 2.76 (1H, m), 2.24-1.72 (18H, m) ppm.

Example 308: Synthesis of(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451), was prepared by the same synthetic scheme illustrated for(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(206) hydrochloride, shown in Example 165 using4-(1-cyclopropylpiperidin-4-yl)aniline (322) hydrochloride. LC-MS (ESI):m/z (M+1) 436.2. UV: λ=263, 272, 304, 335, 372 nm. Proton NMR (CD₃OD): δ7.69 (1H, s), 7.58 (2H, d, J=8.5 Hz), 7.26 (2H, d, J=8.5 Hz), 4.26 (1H,dd, J=13.0; 3.5 Hz), 4.01 (1H, m), 3.75 (2H, d, J=12.5 Hz), 3.54 (1H,m), 3.48 (1H, m), 3.44 (1H, m), 3.35 (2H, m), 2.89 (1H, m), 2.84 (1H,m), 2.20-1.70 (8H, m), 1.10 (2H, m), 0.98 (2H, m) ppm.

Example 309: Synthesis of3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-((3R)-3-(spiro[3.3]heptane-2-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-((3R)-3-(spiro[3.3]heptane-2-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(452), was prepared by the same synthetic scheme illustrated for Example295 using(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451) and spiro[3.3]heptane-2-carboxylic acid. LC-MS (ESI): m/z (M+1)558.9. UV: λ=267, 277, 306, 336, 372 nm.

Example 310: Synthesis of(R)-5-(3-(cyclopentanecarboxamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(cyclopentanecarboxamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(453), was prepared by the same synthetic scheme illustrated for Example295 using(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451) and cyclopentanecarboxylic acid. LC-MS (ESI): m/z (M+1) 532.8. UV:λ=267, 277, 306, 336, 372 nm. Proton NMR (CD₃OD): δ 7.61 (1H, s), 7.58(2H, d, J=8.5 Hz), 7.20 (2H, d, J=8.5 Hz), 4.15 (1H, dd, J=13.0; 3.0Hz), 3.98 (1H, m), 3.89 (1H, m), 3.76 (2H, d, J=12.5 Hz), 3.44-3.34 (3H,m), 2.88-2.81 (2H, m), 2.62 (1H, m), 2.13 (2H, m), 2.02-1.55 (15H, m),1.07-0.98 (4H, m) ppm.

Example 311: Synthesis of(R)-5-(3-(4-chlorobenzamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(4-chlorobenzamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(454), was prepared by the same synthetic scheme illustrated for Example295 using(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451) and 4-chlorobenzoic acid. LC-MS (ESI): m/z (M+1) 574.2 (chloropattern). UV: λ=265, 276, 305, 335, 372 nm.

Example 312: Synthesis of(R)-5-(3-(3-chlorobenzamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(3-chlorobenzamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(455), was prepared by the same synthetic scheme illustrated for Example295 using(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451) and 3-chlorobenzoic acid.

LC-MS (ESI): m/z (M+1) 574.2 (chloro pattern). UV: λ=305, 336, 373 nm.

Example 313: Synthesis of(R)-5-(3-(5-chloronicotinamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(5-chloronicotinamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(455), was prepared by the same synthetic scheme illustrated for Example295 using(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451) and 5-chloronicotinic acid. LC-MS (ESI): m/z (M+1) 575.2 (chloropattern). UV: λ=269, 275, 305, 336, 373 nm. Proton NMR (CD₃OD): δ 8.45(1H, d, J=2.0 Hz), 8.75 (1H, d, J=2.5 Hz), 8.21 (1H, t, J=2.0 Hz), 7.67(1H, s), 7.57 (2H, d, J=8.5 Hz), 7.17 (2H, d, J=8.5 Hz), 4.33 (1H, dd,J=13.5; 3.5 Hz), 4.16 (1H, m), 4.05 (1H, m), 3.73 (2H, d, J=11.0 Hz),3.52 (1H, dd, J=13.0; 8.0 Hz), 3.47-3.43 (2H, m), 3.33 (1H, m),2.87-2.81 (2H, m), 2.17-1.70 (8H, m), 1.04-0.98 (4H, m) ppm.

Example 314: Synthesis of(R)-5-(3-(5-chlorothiophene-2-carboxamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(5-chlorothiophene-2-carboxamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(457), was prepared by the same synthetic scheme illustrated for Example295 using(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451) and 5-chlorothiophenecarboxylic acid. LC-MS (ESI): m/z (M+1) 580.2(chloro pattern). UV: λ=265, 276, 305, 335, 372 nm. Proton NMR (CD₃OD):δ 7.66 (1H, s), 7.57 (2H, d, J=8.5 Hz), 7.54 (1H, d, J=4.5 Hz), 7.17(2H, d, J=8.0 Hz), 7.04 (1H, d, J=4.0 Hz), 4.52 (1H, m), 4.18 (1H, m),4.06 (1H, m), 3.69 (2H, m), 3.25 (2H, m), 3.15 (2H, m), 2.84 (2H, m),2.14-1.70 (8H, m), 1.02-0.98 (4H, m) ppm.

Example 315: Synthesis of(R)-5-(3-(benzo[b]thiophene-2-carboxamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(benzo[b]thiophene-2-carboxamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(458), was prepared by the same synthetic scheme illustrated for Example295 using(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451) and 2-benzothiophenecarboxylic acid. LC-MS (ESI): m/z (M+1) 596.8.UV: λ=301, 336, 372 nm.

Example 316: Synthesis of(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide(459), was prepared by the same synthetic scheme illustrated for Example295 using(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451) and 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid. LC-MS(ESI): m/z (M+1) 601.0. UV: λ=268, 272, 302, 336, 373 nm. Proton NMR(CD₃OD): δ 7.65 (1H, s), 7.57 (2H, d, J=8.5 Hz), 7.31 (1H, s), 7.18 (2H,d, J=8.5 Hz), 4.42 (1H, m), 4.17 (1H, m), 4.04 (1H, m), 3.71 (2H, d,J=11.5 Hz), 3.24 (4H, m), 2.86-2.78 (4H, m), 2.61 (2H, m), 2.10-1.67(12H, m), 1.04-0.98 (4H, m) ppm.

Example 317: Synthesis of(R)-5-(3-(2-naphthamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(2-naphthamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(460), was prepared by the same synthetic scheme illustrated for Example295 using(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451) and 2-naphthalenecarboxylic acid. LC-MS (ESI): m/z (M+1) 590.8.UV: λ=270, 274, 304, 337, 372 nm.

Example 318: Synthesis of(R)-5-(3-biphenyl-4-ylcarboxamidopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-biphenyl-4-ylcarboxamidopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(461), was prepared by the same synthetic scheme illustrated for Example295 using(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451) and biphenyl-4-carboxylic acid. LC-MS (ESI): m/z (M+1) 616.8. UV:λ=268, 289, 299, 335, 373 nm.

Example 319: Synthesis of(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(6-phenylnicotinamido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(6-phenylnicotinamido)piperidin-1-yl)pyrazine-2-carboxamide(462), was prepared by the same synthetic scheme illustrated for Example295 using(R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide(451) and 6-phenylnicotinic acid. LC-MS (ESI): m/z (M+1) 617.5. UV:λ=265, 272, 300, 336, 372 nm.

Example 320: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(4-fluorobenzamido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(4-fluorobenzamido)piperidin-1-yl)pyrazine-2-carboxamide(463), was prepared by the same synthetic scheme illustrated for Example296 using 4-fluorobenzoyl chloride. LC-MS (ESI): m/z (M+1) 586.6. UV:λ=267, 276, 305, 335, 372 nm. Proton NMR (CD₃OD): δ 7.85 (2H, dd, J=9.0;5.5 Hz), 7.68 (1H, s), 7.59 (2H, d, J=8.5 Hz), 7.21-7.15 (4H, m), 4.57(1H, m), 4.44 (1H, m), 4.18-4.11 (2H, m), 3.63 (2H, m), 3.53 (1H, m),3.07 (2H, m), 2.79 (2H, m), 2.21-1.72 (16H, m) ppm.

Example 321: Synthesis of(R)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)-3-(phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)-3-(phenylamino)pyrazine-2-carboxamide(465), was prepared by the same synthetic scheme illustrated for Example179 using N-methyl-N-phenylcarbamoyl chloride and aniline viaintermediate(R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea(464). LC-MS (ESI): m/z (M+1) 446.3. UV: λ=264, 277, 305, 334, 372 nm.

Example 322: Synthesis of(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(4-fluorophenylamino)pyrazine-2-carboxamide

3-Chloro-5-trifluoromethylaniline (3.66 g, 18. 7 mmol) was dissolved in70 mL THE and stirred in an ice bath. To it were added Boc₂O (4.48 g,20.6 mmol) and DMAP (2.51 g, 20.6 mmol). The mixture was stirred forovernight, and was concentrated in vacuo. The residue was taken into 200mL EtOAc, washed with water ×3, dried, rotavaped, and subjected tosilica flash column using 1% MeOH in DCM to get tert-butyl3-chloro-5-(trifluoromethyl)phenylcarbamate (466, 3.37 g, 61%) as awhite solid. It was dissolved in 100 mL dry THF and treated with NaH(60% in mineral oil, 910 mg, 22.8 mmol) at RT for 15 min and theniodomethane (1.42 mL, 22.8 mmol) was added. The mixture was stirred forovernight, concentrated, taken into 200 mL EtOAc, washed with water ×2,dried, concentrated, and subjected to silica flash column using 0 to 5%EtOAc in DCM to isolate the methylation product as an oil. It wastreated with 1:1 TFA/DCM (10 mL/10 mL) at RT for 3 hours, concentratedin vacuo, taken into 200 mL EtAOc and 50 mL 1N NaOH. The organic phasewas separated, washed with water, dried, subjected to silica flashcolumn with 1% MeOH in DCM to isolate3-chloro-N-methyl-5-(trifluoromethyl)aniline (467, 1.76 g, 53%) as anoil.

3-Chloro-N-methyl-5-(trifluoromethyl)aniline (467, 1.24 g, 5.9 mmol) wasdissolved in 15 mL dry toluene. To it was added Et₃N (1.1 mL, 7.9 mmol),and the mixture was stirred in ice bath.

To it was drop-wise added a pre-made solution of triphosgene (2.46 g,8.3 mmol) in 7.5 mL dry toluene. The mixture was then stirred in icebath for 3 hours. EtOAc (120 mL) and water (50 mL) were then poured intothe mixture, and the organic phase was separated. It was washed withsaturated NaHCO₃(aq) solution, dried, concentrated in vacuo to affordcrude 3-chloro-5-(trifluoromethyl)phenyl(methyl)carbamic chloride (468)as an oil.

(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate(87, 950 mg, 2.8 mmol) was treated with 2:1 DCM/TFA (20 mL/10 mL) at RTfor 20 min. The mixture was concentrated in vacuo to dryness as crude(R)-5-(3-aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile (221, TFAsalt). It was dissolved in 18 mL DMF. To it were added DIEA (3.9 mL,22.4 mmol) and then the crude 468 (estimated 5.9 mmol) prepared. Themixture was stirred at RT for 1.5 hour, diluted with 120 mL EtOAc,washed with water and saturated NaHCO₃(aq) solution, dried, concentratedand subjected to silica flash column using 0 to 3.5% MeOH in DCM toisolate(R)-1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methylurea(469) in quantitative yield.

The title compound,(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(4-fluorophenylamino)pyrazine-2-carboxamide(470), was prepared by the same synthetic scheme illustrated for Example179 using(R)-1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methylurea(469) and 4-fluoroaniline. LC-MS (ESI): m/z (M+1) 566.1 (chloropattern). UV: λ=261, 275, 300, 332, 372 nm. Proton NMR (CD₃OD): δ 7.61(1H, s), 7.59-7.56 (2H, m), 7.49-7.47 (3H, m), 7.02-6.99 (2H, m), 4.09(1H, dd, J=13.0; 3.0 Hz), 3.90 (1H, m), 3.85 (1H, m), 3.49-3.42 (2H, m),3.24 (3H, s), 1.98 (1H, m), 1.75 (2H, m), 1.64 (1H, m) ppm.

Example 323: Synthesis of(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(4-(1-cyanocyclopropyl)phenylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(4-(1-cyanocyclopropyl)phenylamino)pyrazine-2-carboxamide(471), was prepared by the same synthetic scheme illustrated for Example322 using 1-(4-aminophenyl)cyclopropanecarbonitrile. LC-MS (ESI): m/z(M+1) 613.2 (chloro pattern). UV: λ=267, 282, 308, 337, 376 nm. ProtonNMR (CD₃OD): δ 7.65-7.63 (3H m), 7.49-7.46 (3H, m), 7.27 (2H, d, J=9.0Hz), 4.12 (1H, dd, J=12, 5; 2.5 Hz), 3.89 (2H, m), 3.54-3.45 (2H, m),3.25 (3H, s), 1.99 (1H, m), 1.81-1.64 (5H, m), 1.39 (2H, m) ppm. In thefinal step, compound(R)-3-(4-(1-carbamoylcyclopropyl)phenylamino)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)pyrazine-2-carboxamide(472) was found as a by-product and isolated as HCl salt.

Example 324: Synthesis of(R)-3-(4-(1-carbamoylcyclopropyl)phenylamino)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-carbamoylcyclopropyl)phenylamino)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)pyrazine-2-carboxamide(472), was found and isolated as a by-product in the final step duringthe preparation of(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(4-(1-cyanocyclopropyl)phenylamino)pyrazine-2-carboxamide(471). LC-MS (ESI): m/z (M+1) 631.2 (chloro pattern). UV: λ=267, 280,308, 337, 373 nm.

Example 325: Synthesis of(R)-N-(1-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide

(R)-5-(3-Aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile (221, HClsalt, 350 mg, 1.28 mmol) was dissolved in 10 mL DMF. To it were addedimidazo[1,2-a]pyridine-6-carboxylic acid (310 mg, 1.92 mmol), DIEA (890μL, 5.12 mmol) and then PyBOP (1.00 g, 1.92 mmol). The mixture wasstirred at RT for 1 hour, diluted with 100 mL EtOAc, washed with water×3, dried, concentrated, and subjected to silica flash column using 0 to7% MeOH in DCM to isolate(R)-N-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide(473). Compound 473 (75 mg, 0.20 mmol) was mixed with4-(tetrahydro-2H-pyran-4-yl)aniline (106 mg, 0.60 mmol), fine-powdercesium carbonate (326 mg, 1.00 mmol), palladium acetate (22 mg, 0.10mmol), BINAP (62 mg, 0.10 mmol) in 15 mL dioxane. The mixture wasdegassed using nitrogen stream for 3 min, and stirred in nitrogenatmosphere at 115° C. for 1 hour. It was cooled to RT, diluted with 50mL EtOAc, stirred and filtered. The filtrate was concentrated andsubjected to silica flash column using 0 to 11% MeOH in DCM to isolate(R)-N-(1-(5-cyano-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide(474). It was dissolved in 10 mL MeOH and 3 mL DMSO. To it were addedone NaOH solid bead (about 100 mg) and 1 mL 30% H₂O₂. The mixture wasstirred at RT for 1.5 hour, quenched with 5 mL MeCN, stirred,concentrated, acidified with 0.3 mL TFA, and directly subjected toreverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobilephases to isolate the title compound,(R)-N-(1-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide(475) (24 mg) as HCl salt, and also the by-product,(R)-N-(1-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)-5-hydroxyimidazo[1,2-a]pyridine-6-carboxamide(476) (15 mg) as HCl salt. For compound 475, LC-MS (ESI): m/z (M+1)541.3. UV: λ=304, 336, 373 nm. Proton NMR (CD₃OD): δ 9.26 (1H, s), 8.30(2H, m), 8.14 (1H, d, J=2.0 Hz), 7.99 (1H, d, J=9.5 Hz), 7.66 (1H, s),7.51 (2H, d, J=9.0 Hz), 7.11 (2H, d, J=9.0 Hz), 4.41 (1H, m), 4.21 (1H,m), 4.10 (1H, m), 3.92 (2H, m), 3.44 (4H, m), 2.66 (1H, m), 2.16 (1H,m), 1.97 (1H, m), 1.84 (1H, m), 1.76 (1H, m), 1.62 (3H, m), 1.56 (1H, m)ppm.

Example 326: Synthesis of(R)-N-(1-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)-5-hydroxyimidazo[1,2-a]pyridine-6-carboxamide

The title compound,(R)-N-(1-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)-5-hydroxyimidazo[1,2-a]pyridine-6-carboxamide(476), was found and isolated as by-product during the preparation of(R)-N-(1-(5-cyano-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide(474) in the final step. LC-MS (ESI): m/z (M+1) 557.3. UV: λ=309, 358,373 nm. Proton NMR (CD₃OD): δ 8.28 (1H, d, J=9.0 Hz), 7.83 (1H, d, J=2.5Hz), 7.60 (1H, s), 7.55 (1H, d, J=2.5 Hz), 7.49 (2H, d, J=9.0 Hz), 7.10(2H, d, J=8.5 Hz), 6.58 (1H, d, J=9.5 Hz), 4.21 (1H, m), 4.17 (1H, m),3.95 (2H, m), 3.83 (1H, m), 3.67 (1H, m), 3.61 (1H, m), 3.49 (2H, m),2.66 (1H, m), 2.14 (1H, m), 1.96 (1H, m), 1.83-1.60 (6H, m) ppm.

Example 327: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)azepan-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)azepan-1-yl)pyrazine-2-carboxamide(478), was prepared by the same synthetic scheme illustrated for Example286 and Example 287 using (R)-3-Boc-aminoazepane. LC-MS (ESI): m/z (M+1)549.8. UV: λ=267, 278, 306, 336, 373 nm. Proton NMR (CD₃OD): δ 7.70-7.63(3H, m), 7.19 (2H, d, J=8.5 Hz), 4.02 (2H, m), 3.71 (2H, d, J=12.5 Hz),3.57-3.53 (2H, m), 3.15-3.11 (2H, m), 2.88-2.78 (9H, m), 2.23 (2H, m),2.13 (2H, m), 2.05-1.93 (4H, m), 1.89-1.59 (9H, m), 1.43 (1H, m) ppm.

Example 328: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(cyclopropanecarboxamido)azepan-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(cyclopropanecarboxamido)azepan-1-yl)pyrazine-2-carboxamide(479), was prepared by the same synthetic scheme illustrated for Example286 and Example 288 using (R)-3-Boc-aminoazepane. LC-MS (ESI): m/z (M+1)546.9.

Example 329: Synthesis of(R)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-3-(3-(3,3-dimethylureido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

To ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (1) (120mg, 0.50 mmol) in acetonitrile (10 mL) was added4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (140 mg, 0.50mmol) and then DIEA (180 μL, 1.0 mmol). The mixture was stirred at RTfor 30 min. To the mixture was then added ammonia (7.0 N solution inmethanol, 15 mL). The mixture turned cloudy in 10 min and then into asuspension. The mixture was stirred for 2 hours, concentrated in vacuoto ½ of the volume, and the solid was isolated by filtration. It waswashed with cold acetonitrile (10 mL×2) and then washed with hexane (10mL×3). The solid was dried in a vacuum oven to afford5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-3-(methylthio)-1,2,4-triazine-6-carboxamide(480) (170 mg, 0.41 mmol, 82% yield) in high purity. It was dissolved in10 mL NMP. To it was added dry mCPBA (77% strength, 320 mg, 1.44 mmol).The mixture was stirred at RT for 2 hours. To the mixture was added DIEA(720 μL, 4.10 mmol) and (R)-(3-BOC-amino)piperidine (3) (170 mg, 0.82mmol). The mixture was stirred at 80° C. for 2 hours. The mixture wascooled to RT, diluted with water 30 mL, extracted with EtOAc 25 mL×5.The combined organic extract phase was washed with brine, dried,concentrated and subjected to silica flash column using 0 to 40% MeOH inDCM to isolate(R)-4-(4-(3-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-6-carbamoyl-1,2,4-triazin-5-ylamino)phenyl)-1-cyclopentylpiperidine1-oxide (481). It was dissolved in 10 mL dry MeCN and 3 mL NMP. To thestirred solution was added bis(pinacolato)diborane (100 mg, 0.39 mmol).The mixture was stirred at RT for 10 min, quenched with 5 mL MeOH,stirred for 30 min, concentrated and subjected to silica flash columnusing 0 to 15% MeOH in DCM to isolate (R)-tert-butyl1-(6-carbamoyl-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate(482) (160 mg, 69% yield for 2 steps). It was treated with 20 mLcommercial 4N HCl in dioxane at RT for 1.5 hour to give(R)-3-(3-aminopiperidin-1-yl)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamidehydrochloride (483) in quantitative yield. Compound 483 (88 mg, 0.19mmol) was dissolved in 5 mL NMP. To it were added DIEA (330 μL, 1.9mmol) and then dimethylcarbamoyl chloride (70 μL, 0.76 mmol). Themixture was stirred at RT for 1.5 hour, quenched with 0.5 mL TFA, anddirectly subjected to reverse phase prep HPLC using 5 mM HCl (aq) andneat MeCN as mobile phases to isolate the title compound,(R)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-3-(3-(3,3-dimethylureido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(484), as HCl salt (49 mg). LC-MS (ESI): m/z (M+1) 536.3. UV: λ=260 nm.

Example 330: Synthesis of(R)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-3-(3-propionamidopiperidin-1-yl)-1,2,4-triazine-6-carboxamide

The title compound,(R)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-3-(3-propionamidopiperidin-1-yl)-1,2,4-triazine-6-carboxamide(485), was prepared by the same synthetic scheme illustrated for Example329 using(R)-3-(3-aminopiperidin-1-yl)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamidehydrochloride (483) and propionyl chloride. LC-MS (ESI): m/z (M+1)521.4. UV: λ=260 nm. Proton NMR (CD₃OD): δ 7.70 (2H, d, J=8.5 Hz), 7.37(2H, d, J=8.5 Hz), 4.28 (1H, dd, J=13.0; 3.5 Hz), 3.99 (1H, m), 3.73(2H, d, J=12.5 Hz), 3.59-3.54 (2H, m), 3.47-3.44 (2H, m), 3.17-3.13 (2H,m), 2.95 (1H, m), 2.25-2.14 (6H, m), 2.06-1.95 (4H, m), 1.88 (2H, m),1.80-1.68 (6H, m), 1.11 (3H, t, J=7.5 Hz) ppm.

Example 331: Synthesis of(R)-5-(4-(4-cyclopentylpiperazin-1-yl)phenylamino)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

The title compound,(R)-5-(4-(4-cyclopentylpiperazin-1-yl)phenylamino)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(486), was prepared by the same synthetic scheme illustrated for Example330 using 4-methoxybenzoyl chloride and4-(4-cyclopentylpiperazin-1-yl)aniline. LC-MS (ESI): m/z (M+1) 600.2.UV: λ=251 nm.

Example 332: Synthesis of(R)-5-(4-(4-(dimethylcarbamoyl)piperidin-1-yl)phenylamino)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

The title compound,(R)-5-(4-(4-(dimethylcarbamoyl)piperidin-1-yl)phenylamino)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(487), was prepared by the same synthetic scheme illustrated for Example330 using 1-(4-aminophenyl)-N,N-dimethylpiperidine-4-carboxamide and4-methoxybenzoyl chloride. LC-MS (ESI): m/z (M+1) 602.2. UV: λ=259 nm.

Example 333: Synthesis of(R)-5-(4-(4-(dimethylcarbamoyl)piperidin-1-yl)phenylamino)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

(R)-tert-Butyl 3-aminopiperidine-1-carboxylate (1.70 g, 8.5 mmol) wasmixed with p-anisic acid (1.42 g, 9.35 mmol) in 5 mL DMF and 25 mLdioxane. The mixture was stirred at RT, and to it were added DIEA (2.07mL, 11.9 mmol) and then PyBOP (4.86 g, 9.35 mmol). The mixture wasstirred at RT for 3 hours, diluted with 150 mL EtOAc, washed with water60 mL×3, dried, concentrated, subjected to silica flash column using 0to 20% EtOAc in DCM to isolate (R)-tert-butyl3-(4-methoxybenzamido)piperidine-1-carboxylate (488) in quantitativeyield. Compound 488 (1.86 g, 5.56 mmol) was treated with 30 mLcommercial 4N HCl in dioxane at RT for 15 min, giving(R)-4-methoxy-N-(piperidin-3-yl)benzamide hydrochloride (489) inquantitative yield as a white solid.

To ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (1) (1.20g, 5.15 mmol) in acetonitrile (40 mL) was added tert-butyl4-(4-aminophenyl)piperidine-1-carboxylate (2.14 g, 7.73 mmol) and thenDIEA (1350 μL, 7.73 mmol). The mixture was stirred at RT for 1 hour. Tothe mixture was then added ammonia (7.0 N solution in methanol, 30 mL).The mixture turned cloudy in 10 min and then into a suspension. Themixture was stirred for 8 hours, and the solid was isolated byfiltration. It was washed with cold acetonitrile (10 mL×2) and thenwashed with hexane (10 mL×3). The solid was dried in a vacuum oven toafford tert-butyl4-(4-(6-carbamoyl-3-(methylthio)-1,2,4-triazin-5-ylamino)phenyl)piperidine-1-carboxylate(490) (1.82 g, 79% yield) in high purity. Compound 490 (600 mg, 1.35mmol) was dissolved in 20 mL NMP. To it were added dry mCPBA (77%strength, 840 mg, 3.38 mmol). The mixture was stirred at RT for 1 hour.To the mixture was added DIEA (2.10 mL, 12.1 mmol) and(R)-4-methoxy-N-(piperidin-3-yl)benzamide hydrochloride (489) (550 mg,2.03 mmol). The mixture was stirred at 70° C. for 30 min. The mixturewas cooled to RT, diluted with 200 mL chloroform, washed with 1N NaOH(aq)×2 and water, dried, concentrated in vacuo to dryness for crude(R)-tert-butyl4-(4-(6-carbamoyl-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazin-5-ylamino)phenyl)piperidine-1-carboxylate(491) (740 mg, 87%). It was treated with 35 mL commercial 4N HCl indioxane at RT for 45 min. The mixture was concentrated in vacuo todryness to afford crude(R)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-5-(4-(piperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide(492). A small amount of crude 492 was purified using reverse phase prepHPLC to isolate as HCl salt. LC-MS (ESI): m/z (M+1) 531.1. UV: λ=255 nm.

Example 334: Synthesis of(R)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

The title compound,(R)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(493), was prepared by the same synthetic scheme illustrated for Example256 using(R)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-5-(4-(piperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide(492). LC-MS (ESI): m/z (M+1) 599.2. UV: λ=257 nm.

Example 335: Synthesis of(R)-5-(4-(piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

The title compound,(R)-5-(4-(piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(494), was prepared by the same synthetic scheme illustrated for Example333 using piperidine-1-carbonyl chloride to replace p-anisic acid/PyBOP.LC-MS (ESI): m/z (M+1) 508.2. UV: λ=261 nm.

Example 336: Synthesis of(R)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

The title compound,(R)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(493), was prepared by the same synthetic scheme illustrated for Example256 using(R)-5-(4-(piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(494). LC-MS (ESI): m/z (M+1) 576.3. UV: λ=265, 323, 337 nm.

Example 337:(R)-5-(4-(1-formylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamidehydrochloride (494) (60 mg, 0.11 mmol) was dissolved in 3 mL DMF. To itwere added formic acid (25 mg, 0.55 mmol), DIEA (200 μL, 1.10 mmol) andthen PyBOP (115 mg, 0.22 mmol). The mixture was stirred at RT for 1hour, quenched with 0.3 mL TFA, and directly subjected to reverse phaseprep HPLC to isolate the title compound,(R)-5-(4-(1-formylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(496), as HCl salt (37 mg). LC-MS (ESI): m/z (M+1) 536.2. UV: λ=261,329, 337 nm.

Example 338:(R)-5-(4-(1-acetylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamidehydrochloride (494) (70 mg, 0.13 mmol) was dissolved in 4 mL DMF. To itwere added DIEA (230 μL, 1.30 mmol) and then acetic anhydride (37 μL,0.39 mmol). The mixture was stirred at RT for 1 hour, quenched with 0.3mL TFA, and directly subjected to reverse phase prep HPLC to isolate thetitle compound,(R)-5-(4-(1-acetylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(497), as HCl salt (47 mg). LC-MS (ESI): m/z (M+1) 550.3. UV: λ=261,329, 337 nm.

Example 339:(R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(4-(1-propionylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide

(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamidehydrochloride (494) (70 mg, 0.13 mmol) was dissolved in 4 mL DMF. To itwere added DIEA (230 μL, 1.30 mmol) and then propionyl chloride (36 μL,0.39 mmol). The mixture was stirred at RT for 1 hour, quenched with 0.3mL TFA, and directly subjected to reverse phase prep HPLC to isolate thetitle compound,(R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(4-(1-propionylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide(498), as HCl salt (45 mg). LC-MS (ESI): m/z (M+1) 564.3. UV: λ=263,329, 338 nm.

Example 340:(R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(4-(1-propionylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide

(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamidehydrochloride (494) (60 mg, 0.11 mmol) was dissolved in 3 mL DMF. To itwere added DIEA (190 μL, 1.10 mmol) and then acryloyl chloride (30 mg,0.33 mmol). The mixture was stirred at RT for 20 min, quenched with 0.3mL TFA, and directly subjected to reverse phase prep HPLC to isolate thetitle compound,(R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(4-(1-propionylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide(499), as HCl salt (35 mg). LC-MS (ESI): m/z (M+1) 562.3. UV: λ=258,329, 337 nm.

Example 341:(R)-5-(4-(1-(2-cyanoacetyl)piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamidehydrochloride (494) (75 mg, 0.14 mmol) was dissolved in 4 mL DMF. To itwere added 2-cyanoacetic acid (36 mg, 0.42 mmol), DIEA (250 μL, 1.40mmol) and then PyBOP (150 mg, 0.28 mmol). The mixture was stirred at RTfor 45 min, quenched with 0.3 mL TFA, and directly subjected to reversephase prep HPLC to isolate the title compound,(R)-5-(4-(1-(2-cyanoacetyl)piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(500), as HCl salt (76 mg). LC-MS (ESI): m/z (M+1) 575.3. UV: λ=262,329, 337 nm.

Example 342:(R)-5-(4-(N,N-dimethylcarbamimidoyl)phenylamino)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

(R)-5-(4-Cyanophenylamino)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(194) (90 mg, 0.18 mmol) was dissolved in 25 mL dry MeOH. It was chilledin an ice bath, and was then charged with HCl gas from a lecture bottleusing a long needle to bubble the gas into the bottom of the solutionuntil saturation reached. The resulting mixture was stirred at RT forovernight, and was placed back to the ice bath for repeated HCl gascharging till saturation. The resulting mixture was stirred for anotherovernight, and concentrated in vacuo to dryness to afford crude(R)-methyl4-(6-carbamoyl-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazin-5-ylamino)benzimidate(501). It was dissolved in 15 mL dry MeOH. To it was added dimethylamine(2M in THF, 1.0 mL). The mixture was sent to 60° C. bath and stirred for1 hour. It was cooled to RT, concentrated in vacuo, acidified with 0.3mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl(aq) and next MeCN as mobile phases to isolate the title compound,(R)-5-(4-(N,N-dimethylcarbamimidoyl)phenylamino)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide(502), as HCl salt (59 mg). LC-MS (ESI): m/z (M+1) 532.2. UV: λ=267 nm.

Example 343: Synthesis of(R)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-5-(4-(imino(pyrrolidin-1-yl)methyl)phenylamino)-1,2,4-triazine-6-carboxamide

The title compound,(R)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-5-(4-(imino(pyrrolidin-1-yl)methyl)phenylamino)-1,2,4-triazine-6-carboxamide(503), was prepared by the same synthetic scheme illustrated for Example342 using pyrrolidine. LC-MS (ESI): m/z (M+1) 558.2. UV: λ=268 nm.

Example 344: Synthesis of(R)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-5-(4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide

The title compound,(R)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-5-(4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide(504), was prepared by the same synthetic scheme illustrated for Example342 using N-methylethylenediamine. LC-MS (ESI): m/z (M+1) 532.2. UV:λ=267 nm.

Example 345:(R)-3-(1-but-2-ynoylpyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide

To a solution of(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(pyrrolidin-3-ylamino)-1,2,4-triazine-6-carboxamide(83) (90 mg, 0.22 mmol) in NMP (4 mL) were 2-butynoic acid (55 mg, 0.66mmol), DIEA (380 μL, 2.2 mmol) and then PyBOP (230 mg, 0.44 mmol). Themixture was stirred at RT for 30 min, quenched with TFA (0.6 mL),diluted with 2 mL water, and subjected to reverse phase preparative HPLCusing 0.1% formic acid in water and neat MeCN to isolate the titlecompound,(R)-3-(1-but-2-ynoylpyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide(505) as formic acid salt. LC-MS (ESI): m/z (M+1) 479.1. UV: λ=280 nm.Proton NMR (CD₃OD): δ 7.87 (2H, m), 7.47 (2H, m), 4.56 (1H, m), 4.07(1H, m), 3.88-3.77 (2H, m), 3.75-3.44 (9H, m), 2.37 (1H, m), 2.15 (1H,m), 2.05 (3H, s) ppm.

Example 346: Synthesis of3-(4-(2-methoxyethoxy)phenylamino)-5-((R)-3-(3-((S)-1-phenylethyl)ureido)piperidin-1-yl)pyrazine-2-carboxamide

To a solution of(R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(2-methoxyethoxy)phenylamino)pyrazine-2-carboxamide(235) (14 mg, 0.03 mmol) in 1 mL NMP in a sealed tube added(S)-(−)-1-phenylethylamine (50 μL). The mixture was stirred in 100° C.bath for overnight. It was acidified with 0.5 mL TFA, and subjected toreverse phase preparative HPLC using 5 mM HCl (aq) and neat MeCN toisolate the title compound,3-(4-(2-methoxyethoxy)phenylamino)-5-((R)-3-(3-((S)-1-phenylethyl)ureido)piperidin-1-yl)pyrazine-2-carboxamide (506) as HCl salt(9.5 mg). LC-MS (ESI): m/z (M+1) 534.2. UV: λ=268, 276, 304, 339, 375nm.

Example 347: Synthesis of3-(4-(2-methoxyethoxy)phenylamino)-5-((R)-3-(3-((R)-1-phenylethyl)ureido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,3-(4-(2-methoxyethoxy)phenylamino)-5-((R)-3-(3-((R)-1-phenylethyl)ureido)piperidin-1-yl)pyrazine-2-carboxamide(507), was prepared by the same synthetic scheme illustrated for Example346 using (R)-(+)-1-phenylethylamine. LC-MS (ESI): m/z (M+1) 534.3. UV:λ=268, 276, 304, 338, 373 nm.

Example 348: Synthesis of(R)-3-(5-carbamoyl-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide

(R)-tert-Butyl-azepan-3-ylcarbamate (250 mg, 1.17 mmol) was dissolved inDMF (0.5 mL), and DIEA (0.41 mL, 2.3 mmol). Dimethylcarbamoyl chloride(0.16 mL, 1.8 mmol) was then added and the reaction was stirred at RTfor 1 hour. An additional aliquot of dimethylcarbamoyl chloride (0.16mL, 1.8 mmol), DIEA (0.41 mL, 2.3 mmol), and DMF (0.5 mL) were added andthe reaction was stirred for 6 hours. The solution was diluted withwater (1 mL) and the solvents were removed under reduced pressure. Theresidue was dissolved in a mixture of EtOAc and H₂O and the aqueouslayer was extracted with EtOAc (×2). The organic extracts were combined,washed with brine, dried, and concentrated. The crude material (300 mg)was dissolved in HCl/dioxane (4 M, 2 mL) and stirred at RT for 1 hour.The solid that formed during the reaction was removed by filtration,suspended in EtOAc, and washed with 1 M NaOH (aq). The aqueous solutionwas then extracted with EtOAc (×3) and the combined organic extractswere washed with brine, dried, and concentrated to give(R)-3-amino-N,N-dimethylazepane-1-carboxamide (508) (˜200 mg crude).

(R)-3-Amino-N,N-dimethylazepane-1-carboxamide (508) (˜200 mg crude) wasdissolved in THF (7 mL), and DIEA (0.30 mL, 1.7 mmol) was added,followed by 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.57 mmol). Thereaction was stirred at RT for 12 hours. The solvents were removed underreduced pressure, and the residue was purified by silica columnchromatography (MeOH, DCM) to give(R)-3-(6-chloro-5-cyanopyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide(509) (53 mg, 0.16 mmol, 14% yield over 3 steps).

(R)-3-(6-Chloro-5-cyanopyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide(509) (53 mg, 0.16 mmol) was combined with 3-methylisothiazol-5-aminehydrochloride (45 mg, 0.39 mmol), Pd(OAc)₂ (14 mg, 0.062 mmol), BINAP(36 mg, 0.058 mmol), and Cs₂CO₃ (196 mg, 0.601 mmol). The solids weresuspended in dioxane (10 mL degassed for 10 minutes with Nitrogensparge) and the resulting suspension was stirred at 115° C. for 4 hours.The reaction mixture was cooled to RT, filtered, and purified byprep-TLC (EtOAc/DCM) to give(R)-3-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide(510) (20 mg, 0.050 mmol, 31% yield).

(R)-3-(5-Cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide(510) (20 mg, 0.050 mmol) was dissolved in 5 mL TFA, and the solutionwas heated to 80° C. Concentrated H₂SO₄ (7 drops) was added dropwise,and the reaction was allowed to stir for 30 min. Additional H₂SO₄ (15drops) was added dropwise and the reaction was allowed to stir for 30minutes. The reaction was cooled to RT, and diluted with 2 mL water and2 mL methanol. The mixture was then directly subjected to reverse phasepreparative HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases, andlyophilized to give(R)-3-(5-carbamoyl-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide(511) (16 mg, 0.038 mmol, 76% yield). LC-MS (ESI): m/z (M+1) 419.6.Proton NMR (DMSO-d₆): δ 12.27 (1H, s), 8.05 (1H, s), 7.81 (1H, s),7.48-7.44 (2H, m), 6.85 (1H, s), 4.46 (1H, m), 3.35 (4H, m), 2.70 (6H,s), 2.30 (3H, s), 2.02 (1H, m), 1.79 (2H, m), 1.70 (1H, m), 1.57 (2H, m)ppm.

Example 349: Synthesis of(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(cyclopropanecarboxamido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(cyclopropanecarboxamido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide(512), was prepared by the same synthetic scheme illustrated for Example234 using (R)-tert-butyl 2-methylpiperidin-3-ylcarbamate (307) andcyclopropanecarbonyl chloride. LC-MS (ESI): m/z (M+1) 546.8. UV: λ=268,277, 306, 335, 372 nm.

Example 350: Synthesis of(R)-3-(cyclopropylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide

(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate(87, 400 mg, 1.20 mmol) was treated with 10 mL 4N HCl in dioxane for 2hours. The mixture was concentrated in vacuo to dryness. It wasdissolved in 3 mL DMF/15 mL dioxane. To it were added DIEA (2.09 mL, 12mmol) and then N-methyl-N-phenylcarbamoyl chloride (610 mg, 3.6 mmol).The mixture was stirred for 3 hours, diluted with 100 mL EtOAc, washedwith water ×3, dried, concentrated and subjected to flash column with 0to 4% MeOH in DCM to isolate(R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea(513, 530 mg) in quantitative yield.

(R)-3-(1-(6-Chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea(513, 100 mg) was dissolved in 4 mL DMSO in a sealed tube. To it wasadded cyclopropylamine (210 μL, 3 mmol) and the mixture was stirred in70° C. bath for 16 hours. It was diluted with 60 mL EtOAc, washed withwater ×2, concentrated in vacuo to afford crude(R)-3-(1-(5-cyano-6-(cyclopropylamino)pyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea(514). It was dissolved in 4 mL MeOH and 2 mL DMSO. To it were added oneNaOH solid pellet (about 50-100 mg) and then 0.5 mL 30% H₂O₂. Themixture was stirred at RT for 45 min, diluted with 10 mL MeCN, stirredfor 5 min, concentrated on rotavap. The residue was treated with 0.3 mLTFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl(aq) and neat MeCN as mobile phases to isolate(R)-3-(cyclopropylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide(515) as HCl salt (74 mg, 67% yield). LC-MS (ESI): m/z (M+1) 410.3. UV:λ=283, 317, 369 nm.

Example 351: Synthesis of(R)-3-(cyclopentylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide

The title compound,(R)-3-(cyclopentylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide(516), was prepared by the same synthetic scheme illustrated for Example350 using cyclopentylamine. It was isolated as HCl salt using reversephase prep HPLC. LC-MS (ESI): m/z (M+1) 438.3. UV: λ=283, 319, 372 nm.

Example 352: Synthesis of(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(cyclopropylamino)pyrazine-2-carboxamide

3-Chloro-5-trifluoromethylaniline (517, 3.66 g, 18. 7 mmol) wasdissolved in 70 mL THF and stirred in an ice bath. To it were addedBoc₂O (4.48 g, 20.6 mmol) and DMAP (2.51 g, 20.6 mmol). The mixture wasstirred for overnight, and was concentrated in vacuo. The residue wastaken into 200 mL EtOAc, washed with water ×3, dried, rotavaped, andsubjected to silica flash column using 1% MeOH in DCM to get tert-butyl3-chloro-5-(trifluoromethyl)phenylcarbamate (518, 3.37 g, 61%) as awhite solid. It was dissolved in 100 mL dry THF and treated with NaH(60% in mineral oil, 910 mg, 22.8 mmol) at RT for 15 min and theniodomethane (1.42 mL, 22.8 mmol) was added. The mixture was stirred forovernight, concentrated, taken into 200 mL EtOAc, washed with water ×2,dried, concentrated, and subjected to silica flash column using 0 to 5%EtOAc in DCM to isolate the methylation product as an oil. It wastreated with 1:1 TFA/DCM (10 mL/10 mL) at RT for 3 hours, concentratedin vacuo, taken into 200 mL EtAOc and 50 mL 1N NaOH. The organic phasewas separated, washed with water, dried, subjected to silica flashcolumn with 1% MeOH in DCM to isolate3-chloro-N-methyl-5-(trifluoromethyl)aniline (519, 1.76 g, 53%) as anoil.

3-Chloro-N-methyl-5-(trifluoromethyl)aniline (519, 1.24 g, 5.9 mmol) wasdissolved in 15 mL dry toluene. To it was added Et₃N (1.1 mL, 7.9 mmol),and the mixture was stirred in ice bath. To it was drop-wise added apre-made solution of triphosgene (2.46 g, 8.3 mmol) in 7.5 mL drytoluene. The mixture was then stirred in ice bath for 3 hours. EtOAc(120 mL) and water (50 mL) were then poured into the mixture, and theorganic phase was separated. It was washed with saturated NaHCO₃(aq)solution, dried, concentrated in vacuo to afford crude3-chloro-5-(trifluoromethyl)phenyl(methyl)carbamic chloride (520) as anoil.

(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate(87, 950 mg, 2.8 mmol) was treated with 2:1 DCM/TFA (20 mL/10 mL) at RTfor 20 min. The mixture was concentrated in vacuo to dryness as crude(R)-5-(3-aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile (221, TFAsalt). It was dissolved in 18 mL DMF. To it were added DIEA (3.9 mL,22.4 mmol) and then the crude 520 (estimated 5.9 mmol) prepared. Themixture was stirred at RT for 1.5 hour, diluted with 120 mL EtOAc,washed with water and saturated NaHCO₃(aq) solution, dried, concentratedand subjected to silica flash column using 0 to 3.5% MeOH in DCM toisolate(R)-1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methylurea(521) in quantitative yield.

(R)-1-(3-Chloro-5-(trifluoromethyl)phenyl)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methylurea(521, 50 mg, 0.10 mmol) was dissolved in 2 mL NMP in a sealed tube. Toit was added cyclopropylamine (210 μL, 3.0 mmol), and the mixture wasstirred in 70° C. bath for overnight. It was diluted with 50 mL EtOAc,washed with saturated NH₄C₁ (aq) solution and water ×2, concentrated invacuo to give crude(R)-1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(1-(5-cyano-6-(cyclopropylamino)pyrazin-2-yl)piperidin-3-yl)-1-methylurea(522). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were addedone NaOH solid pellet (about 50-100 mg) and then 0.5 mL 30% H₂O₂. Themixture was stirred at RT for 1 hour, diluted with 10 mL MeCN, stirredfor 5 min, concentrated on rotavap. The residue was treated with 0.3 mLTFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl(aq) and neat MeCN as mobile phases to isolate(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(cyclopropylamino)pyrazine-2-carboxamide(523 as HCl salt (32 mg, 62% yield). LC-MS (ESI): m/z (M+1) 512.2(chloro pattern). UV: λ=282, 318, 369 nm. Proton NMR (CD₃OD): δ 7.53(1H, m), 7.51 (1H, broad s), 7.48 (1H, broad s), 7.46 (1H, s), 3.98 (1H,dd, J=13.5; 3.5 Hz), 3.90 (1H, m), 3.81 (1H, m), 3.66 (1H, m), 3.52 (1H,m), 3.25 (3H, s), 2.71 (1H, m), 1.96 (1H, m), 1.78 (2H, m), 1.62 (1H,m), 0.76 (2H, m), 0.45 (2H, m) ppm.

Example 353: Synthesis of(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide(525), was prepared by the same synthetic scheme illustrated for Example352 using tetrahydro-2H-pyran-4-amine. It was isolated as HCl salt usingreverse phase prep HPLC. LC-MS (ESI): m/z (M+1) 556.2 (chloro pattern).UV: λ=281, 317, 369 nm.

Example 354: Synthesis of(R)-5-(3-(3-(tetrahydro-2H-pyran-4-yl)ureido)piperidin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide

The title compound,(R)-5-(3-(3-(tetrahydro-2H-pyran-4-yl)ureido)piperidin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide(526), was found and isolated as a major by-product during the finalstep of the preparation of(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide(525). It was isolated as HCl salt using reverse phase prep HPLC. LC-MS(ESI): m/z (M+1) 448.3. UV: λ=281, 317, 369 nm.

Example 355a: Btk in vitro Inhibitory Activity (method A)

The Btk IC₅₀s of compounds disclosed herein is determined in both acellular kinase assay and in a cellular functional assay of BCR-inducedcalcium flux as described below.

Btk kinase activity is determined using a time-resolved fluorescenceresonance energy transfer (TR-FRET) methodology. Measurements areperformed in a reaction volume of 50 μL using 96-well assay plates.Kinase enzyme, inhibitor, ATP (at the K_(m) for the kinase), and 1 μMpeptide substrate (Biotin-AVLESEEELYSSARQ-NH₂ (SEQ ID NO: 1)) areincubated in a reaction buffer composed of 20 mM Tris, 50 mM NaCl, MgCl₂(5-25 mM depending on the kinase), MnCl₂ (0-10 mM), 1 mM DTT, 0.1 mMEDTA, 0.01% bovine serum albumin, 0.005% Tween-20, and 10% DMSO at pH7.4 for one hour. The reaction is quenched by the addition of 1.2equivalents of EDTA (relative to divalent cation) in 25 μL of 1× Lancebuffer (Perkin-Elmer). Streptavidin-APC (Perkin-Elmer) and Eu-labeledp-Tyr100 antibody (Perkin-Elmer) in 1× Lance buffer are added in a 25 μLvolume to give final concentrations of 100 nM and 2.5 nM, respectively,and the mixture is allowed to incubate for one hour. The TR-FRET signalis measured on a multimode plate reader with an excitation wavelength(λ_(Ex)) of 330 nm and detection wavelengths (λ_(Em)) of 615 and 665 nm.Activity is determined by the ratio of the fluorescence at 665 nm tothat at 615 nm. For each compound, enzyme activity is measured atvarious concentrations of compound. Negative control reactions areperformed in the absence of inhibitor in replicates of six, and twono-enzyme controls are used to determine baseline fluorescence levels.Inhibition constants, K_(i)(app), were obtained using the programBatchK_(i) (Kuzmic et al. (2000), Anal. Biochem. 286:45-50). IC₅₀s areobtained according to the equation:

IC ₅₀ ={Ki(app)/(1+[ATP]/K _(m) ^(ATP))}+[E]_(tota) l/2;

For all kinases, [ATP]=K_(m) ^(ATP), [Btk]_(tota)l=0.5 nM and[Lck]_(tota)l=6 nM.

Example 355b: Btk In Vitro Inhibitory Activity (Method B)

Kinase activity is measured in vitro using electrophoretic mobilityshift assay. The kinase reactions are assembled in a total volume of 25μL in 384 well plates. The reactions comprise: BTK enzyme (1 nM,N-terminal His6-tagged (SEQ ID NO: 3), recombinant, full-length, humanBTK purified from baculovirus Sf21 insect cell system), inhibitor, ATP(16 μM, the apparent K_(m) for the kinase), fluorescently labeledpeptide substrate (1 M, FAM-GEEPLYWSFPAKKK-NH2 (SEQ ID NO: 3)) in areaction buffer composed of 100 mM HEPES, pH7.5, 5 mM MgCl₂ 1 mM DTT,0.1% bovine serum albumin, 0.01% Triton X-100, and 1% DMSO. The reactionis incubated for one hour and is quenched by the addition of 45 μL oftermination buffer (100 mM HEPES, pH7.5, 0.01% Triton X-100, 30 mMEDTA). The terminated reactions are analyzed using 12 channel LabChip®3000 microfluidic detection instrument (Caliper Life Sciences). Theenzymatic phosphorylation of the peptide results in a change in netcharge, enabling electrophoretic separation of product from substratepeptide. As substrate and product peptides are separated, two peaks offluorescence are observed. Change in the relative fluorescence intensityof the substrate and product peaks is the parameter measured, reflectingenzyme activity. In the presence of an inhibitor, the ratio betweenproduct and substrate is altered: the signal of the product decreases,while the signal of the substrate increases.

Activity in each sample is determined as the product to sum ratio (PSR):P/(S+P), where P is the peak height of the product peptide and S is thepeak height of the substrate peptide. For each compound, enzyme activityis measured at various concentrations (12 concentrations of compoundspaced by 3× dilution intervals). Negative control samples(0%-inhibition in the absence of inhibitor) and positive control samples(100%-inhibition, in the presence of 20 mM EDTA) are assembled inreplicates of four and are used to calculate %-inhibition values foreach inhibitor at each concentration. Percent inhibition (P_(inh)) isdetermined using following equation:

P _(inh)=(PSR _(0%) −PSR _(inh))/(PSR _(0%) −PSR _(100%))*100,

where PSR_(inh) is the product sum ratio in the presence of inhibitor,PSR_(0%) is the average product sum ration in the absence of inhibitorand PSR_(100%) is the average product sum ratio in 100%-inhibitioncontrol samples;

The IC50 values of inhibitors are determined by 4 parameter sigmoidaldose-response model fitting of the inhibition curves (P_(inh) versusinhibitor concentration) using XLfit 4 software.

Example 355c: Btk In Vitro Inhibitory Activity (Method C)

Human Btk kinase (Genbank accession # NP_000052) was purified frominsect cells as a full-length construct containing a N-terminal 6X-Histag (SEQ ID NO: 2). Btk kinase activity was determined using aradiometric filter binding assay. Measurements are performed in a low μLreaction volume 384-well assay plates. BTK enzyme (8 nM final inreaction), inhibitor (at requested doses), and 0.2 mg/mL peptidesubstrate (Poly-Glu-Tyr, 4:1 ratio) are incubated in a reaction buffercomposed of 20 mM Hepes (pH 7.5), 10 mM MgCl₂, 1 mM EGTA, 0.02% Brij35,0.02 mg/ml BSA, 0.1 mM Na₃VO₄, 2 mM DTT, 1% DMSO for 15 min. followed byaddition of 1 μM ATP to start the assay. Kinase reactions are carriedout for 120 min. at room temperature. The reaction was stopped byspotting of reaction sample onto P81 cationic exchange paper (Whatman).Unbound phosphate was removed by extensive washing of filters in 0.75%Phosphoric acid. After subtraction of background derived from controlreactions containing inactive enzyme (via addition of saturating EDTA),kinase activity data for each dose of compound tested was expressed asthe percent of remaining kinase activity in test samples compared tovehicle (dimethyl sulfoxide) reactions. IC₅₀ values and curve fits wereobtained using Prism (GraphPad Software).

The degree of Btk inhibition was determined using one of the methodsoutlined in Example 355a, 355b and 355c.

TABLE 1 BTK IC₅₀ Values for Exemplary Compounds of the Invention BTKExample # IC₅₀ 1 D 2 A 3 B 4 A 5 A 6 A 7 B 8 A 9 A 10 A 11 A 12 A 13 B14 A 15 B 16 A 17 A 18 B 19 A 20 B 21 B 22 A 23 B 24 B 25 B 26 B 27 B 28B 29 B 30 B 31 B 32 B 33 B 34 B 35 B 36 B 37 B 38 B 39 B 40 B 41 A 42 C43 C 44 B 45 C 46 B 47 A 48 C 49 C 50 C 51 C 52 C 53 D 54 D 55 A 56 C 57C 58 B 59 B 60 C 61 D 62 B 63 A 64 A 65 A 66 A 67 A 68 C 69 B 70 A 71 B72 A 73 A 74 A 75 A 76 C 77 B 78 A 79 B 80 B 81 B 82 B 83 C 84 B 85 B 86A 87 B 88 A 89 A 90 B 91 B 92 A 93 A 94 A 95 B 96 B 97 B 98 B 99 A 100 A101 A 102 A 103 A 104 B 105 A 106 A 107 A 108 C 109 C 110 B 111 B 112 B113 B 114 C 115 A 116 B 117 A 118 B 119 B 120 B 121 B 122 A 123 A 124 A125 A 126 A 127 B 128 A 129 A 130 A 131 A 132 A 133 A 134 A 135 A 136 B137 B 138 A 139 A 140 A 141 A 142 B 143 B 144 A 145 A 146 B 147 A 148 A149 B 150 A 151 A 152 A 153 A 154 A 155 A 156 A 157 A 158 A 159 C 160 B161 A 162 A 163 A 164 A 165 A 166 A 167 A 168 A 169 A 170 A 171 A 172 A173 B 174 B 175 A 176 A 177 A 178 A 179 B 180 C 181 B 182 C 183 C 184 D185 C 186 B 187 B 188 A 189 B 190 B 191 B 192 B 193 B 194 A 195 A 196 B197 A 198 B 199 A 200 A 201 B 202 A 203 A 204 B 205 B 206 A 207 B 208 A209 B 210 A 211 B 212 C 213 B 214 A 215 A 216 B 217 B 218 A 219 B 220 B221 A 222 A 223 A 224 A 225 A 226 B 227 B 228 B 229 B 230 B 231 C 232 A233 C 234 A 235 C 236 A 237 A 238 A 239 A 240 A 241 A 242 A 243 A 244 A245 A 246 A 247 A 248 A 249 A 250 A 251 A 252 A 253 A 254 A 255 A 256 A257 A 258 A 259 A 260 A 261 B 262 B 263 A 264 A 265 A 266 A 267 A 268 A269 A 270 A 271 A 272 A 273 A 274 A 275 A 276 A 277 A 278 A 279 A 280 A281 A 282 A 283 A 284 A 285 A 286 B 287 B 288 B 289 B 290 B 291 C 292 B293 B 294 C 295 A 296 A 297 A 298 A 299 A 300 B 301 B 302 B 303 A 304 A305 A 306 A 307 A 308 C 309 C 310 B 311 A 312 A 313 A 314 B 315 B 316 A317 B 318 B 319 A 320 A 321 C 322 C 323 C 324 B 325 A 326 A 327 A 328 A329 A 330 A 331 A 332 A 333 A 334 A 335 A 336 A 337 A 338 A 339 A 340 A341 A 342 B 343 A 344 B 345 A 346 B 347 B 348 B 349 A 350 D 351 D 352 D353 D 354 D IC₅₀: A ≤ 10 nM; 10 nM < B ≤ 100 nM; 100 nM < C ≤ 1 μM; 1 μM< D ≤ 10 μM; E > 10 μM

Example 356: Inhibition of a Panel of Kinases

The degree of inhibition of a panel of kinases is determined using thein vitro HotSpot kinase assay (purified enzymes, ³³P-ATP, an appropriatesubstrate and 1 uM ATP).

TABLE 2 IC₅₀ Values for Exemplary Compounds of the Invention Compd BtkBtk C481S EGFR LCK JAK3 ID (IC₅₀) (IC₅₀) (IC₅₀) (IC₅₀) (IC₅₀)  47 A N/AE A N/A  48 C N/A E E N/A  55 B N/A E A N/A  70 A C B C A  74 A N/A C CB  75 A N/A D C D  78 A N/A D C N/A  79 B N/A N/A C N/A  80 B N/A N/A CN/A  81 B N/A C N/A D  82 B N/A N/A C D  83 C N/A N/A D C  84 B N/A E DN/A  85 B N/A D C N/A  86 A N/A E C N/A  87 B N/A E C N/A  88 A N/A N/AC N/A  89 A N/A N/A C N/A  90 B N/A N/A C N/A  91 B N/A N/A C N/A  92 AN/A N/A C C  93 A N/A N/A C C  94 A N/A N/A C C  95 B N/A N/A C C  97 BN/A N/A C C  98 B N/A N/A C C  99 A N/A D D C 100 A N/A N/A C C 101 AN/A N/A D N/A 102 A N/A N/A C C 103 B N/A N/A D C 104 B N/A E C N/A 105A N/A D B C 106 A N/A C B C 107 A N/A D B D 108 C N/A N/A D E 109 C N/AN/A D E 110 B N/A E E E 111 B N/A N/A E E 112 B N/A E E E 113 B N/A N/AE E 114 C N/A N/A E E 115 A N/A N/A N/A C 117 A N/A N/A E C 118 B N/AN/A D C 119 B N/A N/A C C 120 B N/A E E E 121 B N/A E E E 122 A N/A N/AE C 123 A N/A N/A D C 124 B N/A E E E 125 A N/A N/A D D 126 B N/A N/A DC 127 B N/A N/A E C 128 A N/A N/A D C 129 A N/A E C C 130 A N/A D C C131 A A C B B 132 A N/A C B B 133 A B E C C 134 A N/A N/A B B 135 A AN/A B B 136 B N/A N/A D E 137 B N/A N/A D E 138 A N/A N/A D C 139 A B EE C 140 A N/A N/A C E 141 A B N/A E E 142 B N/A E N/A D 143 B N/A N/A EE 144 A A N/A C B 145 A N/A N/A D C 146 B N/A N/A C N/A 147 A N/A N/A CN/A 148 A N/A D C C 149 B N/A C N/A D 150 A N/A D C C 151 A B D C C 152A B D C C 153 A B D C C 154 A B D C C 155 A B D B B 156 A N/A D C D 157A N/A D C C 159 C N/A E E E 161 A N/A N/A E C 162 B N/A N/A C D 163 AN/A N/A B C 164 A N/A N/A E D 165 A N/A C B C 166 A N/A D C C 167 A N/AD C C 168 A N/A C B C 170 A B D D C 171 A B D C C 172 A B D C C 173 B BN/A N/A B 174 B B D C C 175 A B D C B 176 A B D C C 177 A B C C C 178 AB D C C 179 B C N/A N/A D 182 C D N/A N/A E 183 C D N/A N/A E 184 C D EE E 185 C C E D D 186 B C N/A E D 187 B B N/A C C 188 A B N/A D C 189 BB D D C 190 B C N/A D D 191 B B N/A C C 192 B C N/A D D 193 B B D C C194 A B D D C 195 A B D D C 196 B C N/A N/A C 197 A B N/A N/A C 198 B BN/A N/A C 199 A B N/A C C 200 A B N/A C C 201 B B E C D 202 A B D C C203 A B N/A N/A C 204 B B D C D 205 B N/A N/A C C 206 A B C C C 207 B BD C C 208 A B D C C 210 A B D C B 211 B C E E C 212 C C N/A N/A D 213 BB N/A N/A B 214 A B N/A N/A C 215 A B N/A N/A C 216 B B E D D 217 B B EC D 218 A B D B C 219 B B D C C 220 B B D C C 221 A A D B C 222 A A N/AN/A B 223 A B N/A N/A C 224 A A N/A N/A C 225 B N/A N/A C C 226 B N/AN/A C C 227 B N/A N/A C C 228 B N/A N/A E C 229 B N/A N/A D C 230 B BN/A N/A B 231 C C N/A N/A C 232 A A C B B 233 C C E C C 234 A A N/A N/AB 235 C C N/A N/A C 236 A B C B B 237 A A N/A N/A C 238 A A N/A B B 239A B N/A C C 240 A A C C C 241 A A D C C 242 A A N/A C C 243 A B N/A C C244 A A N/A C C 245 A A C B B 246 A A C B B 247 A A C B B 248 A A N/AN/A C 249 A A N/A N/A C 250 A A N/A A B 251 A A N/A A B 252 A A N/A A B253 A A B A B 254 A A N/A A B 255 A A N/A B B 256 A A C B B 257 A N/AN/A N/A B 258 A B N/A B B 259 A B N/A B B 260 A A N/A C B 261 B B N/A DD 261 B C N/A D C 263 A A D B B 264 A A D B B 265 A A C B B 266 A A C BB 267 A A C B B 268 A A C C B 269 A A C C B 270 A A C C C 271 A A N/A BB 272 A A N/A B B 273 A A N/A B B 274 A A N/A B B 275 A A D B B 276 A AD B C 277 A B N/A B B 278 A B N/A B B 279 A B N/A B B 280 A A N/A A B281 A A C B B 282 A A N/A B B 283 A A C B B 284 A A C B B 285 A A D B B286 B B N/A B B 287 B B N/A B B 288 B B N/A B B 289 B B D B C 290 B CN/A C D 291 C C N/A B B 292 B C N/A C C 293 B B N/A B B 294 C C C B B295 A B C B B 296 A B N/A B B 297 A N/A N/A N/A C 298 A B C C B 299 A AD C B 300 B B C B B 302 B B N/A N/A C 303 A A C B B 304 A A N/A B B 305A A C B B 306 A A C B B 307 A A D B B 308 C C N/A N/A C 309 C C N/A N/AD 310 B B N/A N/A C 311 A B N/A N/A E 312 A B N/A N/A C 313 A A N/A N/AB 314 B C N/A N/A E 315 B B N/A N/A E 316 A A N/A N/A E 317 B B N/A N/AE 318 B C N/A N/A E 319 A B N/A N/A E 320 A A N/A B B 321 C E N/A N/A E322 C E D D E 323 C C E D E 324 B B E C E 325 A N/A N/A C B 326 A N/AN/A D C 327 A A C B A 328 A B C B A 329 A B N/A B B 330 A B N/A B B 336A N/A C C B 337 A N/A D C B 338 A N/A D C B 339 A N/A D C B 341 B N/A DC C 342 B N/A D D C 343 A N/A D C C 344 B N/A D C C 345 A C D C C IC₅₀:A ≤ 10 nM; 10 nM < B ≤ 100 nM; 100 nM < C ≤ 1 μM; 1 μM < D ≤ 10 μM; E >10 μM

Example 357: Pharmaceutical Compositions

The compositions described below are presented with a compound ofFormula (IA), Formula (I), Formula (Ia), Formula (II), Formula (III),Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb) for illustrativepurposes.

Example 357a: Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula (IA), Formula (I), Formula (Ia), Formula (II),Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb)is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline.The mixture is incorporated into a dosage unit form suitable foradministration by injection.

Example 357b: Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (IA), Formula (I), Formula (Ia), Formula (II),Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb)is mixed with 750 mg of starch. The mixture is incorporated into an oraldosage unit for, such as a hard gelatin capsule, which is suitable fororal administration.

Example 357c: Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of Formula (IA), Formula (I),Formula (Ia), Formula (II), Formula (III), Formula (IV), Formula(Va)-(Vh), or Formula (VIa)-(VIb) with 420 mg of powdered sugar mixed,with 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42 mLmint extract. The mixture is gently blended and poured into a mold toform a lozenge suitable for buccal administration.

Example 357d: Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of Formula (IA), Formula (I), Formula (Ia), Formula (II),Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb)is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodiumchloride solution. The mixture is incorporated into an inhalationdelivery unit, such as a nebulizer, which is suitable for inhalationadministration.

Example 357e: Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of Formula (IA), Formula (I), Formula (Ia), Formula (II),Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb)is mixed with 2.5 g of methylcellulose (1500 mPa), 100 mg ofmethylparapen, 5 g of glycerin and 100 mL of purified water. Theresulting gel mixture is then incorporated into rectal delivery units,such as syringes, which are suitable for rectal administration.

Example 357f: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (IA), Formula (I), Formula (Ia), Formula (II),Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb)is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propyleneglycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP.The resulting gel mixture is then incorporated into containers, such astubes, which are suitable for topical administration.

Example 357g: Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound of Formula (IA), Formula (I), Formula (Ia), Formula (II),Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb)is mixed with 0.9 g of NaCl in 100 mL of purified water and filteredusing a 0.2 micron filter. The resulting isotonic solution is thenincorporated into ophthalmic delivery units, such as eye dropcontainers, which are suitable for ophthalmic administration.

Example 358: Clinical Trial of the Safety and Efficacy of a Compound ofFormula (IA), Formula (I), Formula (Ia), Formula (II), Formula (III),Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb) in RheumatoidArthritis Patients

The purpose of this study is to determine the safety and efficacy of acompound of Formula (IA), Formula (I), Formula (Ia), Formula (II),Formula (III), Formula (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb)in patients with rheumatoid arthritis.

Inclusion Criteria

-   -   Adult males/Females aged 18-80 years.    -   Patients who are taking NSAIDs for the treatment of rheumatoid        arthritis.    -   Patients who belong to ACR functional class 1, 2, 3.

Exclusion Criteria

-   -   Patients who belong to ACR functional class 4.    -   Patients who are hypersensitive to clinical trial medicines or        excipient.    -   Patients who have experience of Cerebrovascular bleeding,        bleeding disorder.

Study Design

-   -   Allocation: Randomized, placebo-controlled.    -   Intervention Model: Single Group Assignment.    -   Masking: Double Blind (Subject, Caregiver).    -   Primary Purpose: Supportive Care.

Primary Outcome Measures

-   -   Changes in '100 mm pain VAS' value from baseline [Time Frame:        −14, 0, 14, 28, 42 day][Designated as safety issue: No].    -   Determine PK of an orally administered compound of Formula (IA),        Formula (I), Formula (Ia), Formula (II), Formula (III), Formula        (IV), Formula (Va)-(Vh), or Formula (VIa)-(VIb).

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1-20. (canceled)
 21. A compound, wherein the compound is(R)-3-(1-(4-tert-butylbenzoyl)piperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide.